Effects of estrogen replacement therapy on the myelin sheath ultrastructure of myelinated fibers in the white matter of middle‐aged ovariectomized rats

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Researchers previously reported an age‐related decline in cognitive function in the aged brain, which was accelerated in women with low levels of estrogen after menopause (Brinton, Yao, Yin, Mack, & Cadenas, 2015; Halbreich et al., 1995). Women who experience early menopause are more likely to develop dementia at a younger age (Ryan et al., 2014). Epidemiological studies showed that estrogen replacement therapy (ORT) could significantly reduce the number of perimenopausal women who developed Alzheimer's disease (Paganini‐Hill & Henderson, 1996; Tang et al., 1996). Furthermore, positive effects of ORT on cognitive behavior have been observed not only in postmenopausal women (Daniel, Witty, & Rodgers, 2015; Sherwin, 2006) but also in both non‐human primates (Lacreuse, Mong, & Hara, 2015; Rapp, Morrison, & Roberts, 2003) and rodents (Frick, 2009; Liu et al., 2015; Luo et al., 2016) after natural menopause or oophorectomy‐induced menopause. In addition, the traditional view was that there was significant loss of the neurons in the cerebral cortex of the aged brain (Brody, 1955; Peters, Morrison, Rosene, & Hyman, 1998). However, stereological studies showed that neuronal death was not significant in the aged cerebral cortex, but there was shrinkage in the volume of aged white matter (Pakkenberg & Gundersen, 1997). Moreover, some researchers reported that the age‐related decline in white matter volume was mainly due to the decline in the total length of myelinated fibers in white matter (Marner, Nyengaard, Tang, & Pakkenberg, 2003; Tang, Nyengaard, Pakkenberg, & Gundersen, 1997). Shrinkage in the volume of white matter in the aged brain has been detected (Pakkenberg & Gundersen, 1997), and a retrospective cohort study revealed that menopause was significantly associated with leukoaraiosis and that a loss of estrogen might play an important role in the development of leukoaraiosis (Seo et al., 2013). How would estrogen supplementation affect white matter structure? Using high‐resolution magnetic resonance imaging (MRI) and optimized voxel methods, scholars found that ORT in postmenopausal women could protect brain structures, including white matter (Erickson et al., 2005). It was also reported that long‐term ORT could reduce white matter loss in ageing (Ha, Xu, & Janowsky, 2007). In contrast, another study noted that ORT did not reduce the age‐related loss in white matter or corpus callosum volume in postmenopausal women and even exacerbated brain atrophy (Low et al., 2006). Thus, the effect of ORT on white matter remained controversial. What might be the reasons for the opposite effects of ORT on white matter? The type, initiation time, and duration of ORT might partly explain the differences in the activities of estrogen in the brain (Sherwin & Henry, 2008). In addition, in a cuprizone diet‐induced mouse model of experimental autoimmune encephalomyelitis, estrogen treatment protected against demyelination, sustained myelination, and promoted remyelination in the corpus callosum (Crawford et al., 2010). Our previous study showed that 1 month of ORT had significant beneficial effects on the myelin sheath volume of myelinated fibers in the white matter of middle‐aged ovariectomized (OVX) rats (Luo et al., 2016). However, the effects of the ORT on the myelin sheath ultrastructure remained unknown. Therefore, in the present study, modern stereological methods were used to investigate the effects of ORT on the myelin sheath ultrastructure of myelinated fibers in the white matter of middle‐aged OVX rats.
17β‐Estradiol (estradiol, E2) is the most important estrogen in women of childbearing age and is the main material in ORT (Chakraborty & Gore, 2004; Feng, Cheng, & Zhang, 2004). The Women's Health Initiative Memory Study (WHIMS) reported that the postmenopausal women who received ORT might be at an increased risk of developing gynecological tumors (Espeland et al.
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