The effect of estrogens and antiestrogens in rat models of hot flush

Abstract

Rat models of hot flush provide important preclinical tools for evaluating the effect of estrogens and the selective estrogen receptor modulators (SERM), including tamoxifen, raloxifene, and tibolone, some of which have received renewed attention as agents to treat neurodegenerative diseases. The first rat model of hot flush is the ovariectomized morphine-dependent model. When morphine is withdrawn with the opioid antagonist naloxone, temperature of the tail is increased by 4-61C (''hot flush''). Estrogens reduce the elevation of tail skin temperature significantly. Tamoxifen functions as a partial agonist, whereas raloxifene functions as anti-estrogen in this animal model. However, when coadministered with estrogen, both tamoxifen and raloxifene antagonize estrogen's action. The second model is based on the diurnal change in tail skin temperature of intact rats, which is 61C lower during the active phase (lights off) than in the passive phase (lights on) of the day. Ovariectomy affects tail skin temperature of the rats' active but not their passive phase, and skin temperature drops only 11C instead of the 61C measured in intact, cycling rats. Estrogen and tibolone restore the changes in tail skin temperature to that present in intact rats; however, raloxifene functions as anti-estrogen in this model. Although neither of the two models exactly recapitulates the hot flush occurring in humans, the heat-dissipating mechanisms are probably similar. Thus, both models can be used to evaluate the estrogenic versus antiestrogenic nature of estrogen receptor ligands, and both models, therefore, provide valuable preclinical tools for drug discovery aimed at identifying compounds to alleviate hot flushes in humans. Drug Dev.

Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model

“…EE treatment at this high dose (1 mg/kg body weight), on the other hand, produced an approximate 50% decrease in TST increase at this time point compared to the control group upon Nlx challenge, while an approximate 25% decrease was observed in this measure with the significantly lower dose of prodrug (300 µg/kg body weight, p.o.). Although these changes were less than what we observed by using OVX rats [17,[25][26][27] and required a 5 to 10 times higher EE dose to observe attenuation of the effect caused by morphine withdrawal, nevertheless it represented discernible decreases in TST in relation to the no drug treatment. We also found that areas under the TST-time curves (AUCs) were more reliable to assess the effect of the drug treatment than temperature recorded at a somewhat arbitrarily preselected time point such as 15 min after the injection of Nlx.…”

“…We have previously described the pharmacological hot flush model adopted for the purpose of drug discovery and early phase development using OVX rats [16,17,25,27]. To our knowledge, this is, however, the first report involving ORDX rats in this context (Figure 3).…”

“…Our chosen animal model was validated with the clinically used EE to confirm the desired effect of exogenous estrogen on lowering TST [17,[25][26][27] in a male rat pharmacological hot flush model for the first time. In this paradigm, morphine-dependent ORDX animals received twice daily (b.i.d.)…”

“…Recently, an ewe model was also proposed to study peripheral skin temperature changes associated with menopause [24]. On the other hand, owing to the close association between estrogens and thermoregulation in several species, the use of convenient rodent models has been suitable to evaluate the effects of novel preclinical therapies focused on hot flushes [17,[25][26][27]. Since rats dissipate heat through the skin of their tail, measuring changes in TST following ovariectomy is an established model for characterizing this most prominent vasomotor symptom (hot flushes)-especially for evaluating potential pharmacological interventions [17,25].…”

“…Since rats dissipate heat through the skin of their tail, measuring changes in TST following ovariectomy is an established model for characterizing this most prominent vasomotor symptom (hot flushes)-especially for evaluating potential pharmacological interventions [17,25]. Morphine-addicted and withdrawn OVX rats have been especially useful due to similarities in symptoms between opioid withdrawal and hot flushes [17,[25][26][27]. In the present study, we utilized this model for studying the utility of the orally (p.o.)…”