Estrogen Mimics – Essay Example
Estrogen Mimics – Essay Example
Any small disturbances in endocrine function, especially during certain stages of the life cycle such as development, pregnancy, and lactation, can lead to profound and lasting effects (Kavlock, et al. 1996, 1-26). For example, estrogen is a hormone secreted primarily by the ovaries. It controls the menstrual cycle, fertility, and maintenance of a healthy pregnancy, among other critical activities in adults. In the fetus, estrogen is essential for the normal development of both males and females (NRDC, N.D.).
Scientists have identified dozens of human-made chemicals that can disrupt the endocrine system. For instance, some man-made chemicals can act like estrogen in the body and are called “estrogen mimics”. Agricultural chemicals such as pesticides, herbicides, and fungicides are commonly known to mimic the activities of estrogen. These are being increasingly detected in agricultural runoff. Besides, effluent from water treatment plants often from drugs flushed down the toilet in homes and pollution from manufacturers including plastics factories and paper pulp mills are also known for estrogen-mimicking properties. Estrogen Mimics – Essay Example. These chemicals are also turning up in aquatic animals and birds that live in or near streams, rivers and the ocean. They are known — in certain concentrations — to disrupt the ability of alligators, frogs, birds and fish to mature and reproduce (Earth and Sky, 2000).
Synthetic substances that can have the same effect as naturally occurring hormones in the body are called “hormone mimics” or “hormonally active agents (HAAs)” as the U.S. National Academy of Sciences termed them in a landmark report issued in August 1999. HAAs may be beneficial, such as the synthetic hormone drugs, estrogen and progesterone, that are found in birth control pills and in hormone replacement therapy taken by women after menopause.
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The classic view of estrogen actions in the brain was confined to regulation of ovulation and reproductive behavior in the female of all mamamalian species studied, including humans. Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes. Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. Estrogen-based therapy therefore holds considerable promise for brain disorders that affect both men and women. However, as investigations are beginning to consider the role of estrogens in the male brain more carefully, it emerges that they have different, even opposite, effects as well as similar effects in male and female brains. This review focuses on these differences, including sex dimorphisms in the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition, which, we argue, are due in a large part to sex differences in the organization of the underlying circuitry. There are notable sex differences in the incidence and manifestations of virtually all central nervous system disorders, including neurodegenerative disease (Parkinson’s and Alzheimer’s), drug abuse, anxiety, and depression. Understanding the cellular and molecular basis of sex differences in brain physiology and responses to estrogen and estrogen mimics is, therefore, vitally important for understanding the nature and origins of sex-specific pathological conditions and for designing novel hormone-based therapeutic agents that will have optimal effectiveness in men or women. Estrogen Mimics – Essay Example.
I. Introduction
The last decade has seen a revolution in our understanding of the actions of estrogen in the body. More than 60 years ago, estrogen, produced by the ovaries, was identified as “the woman’s hormone,” leading to its use as hormone replacement therapy (HRT1) for menopausal/postmenopausal symptoms (hot flashes, night sweats, and vaginal dryness and atrophy). Along the way, scores of anecdotal and retrospective case studies fuelled its reputation to combat diseases of aging (at least in women), including cardiovascular disease (Sullivan and Fowlkes, 1996), osteoporosis (Riggs and Melton, 1995), and Alzheimer’s disease (Sherwin, 2002; Brinton, 2004). This spawned a billion-dollar industry in HRT and opened up the prospect that tissues other than the female reproductive tract, particularly the brain, are important targets for estrogen’s actions. Our perception of the roles of estrogen in the male has also expanded with the realization that it can be synthesized locally from steroid precursors, including circulating testosterone, by aromatase enzymes in many tissues (Sharpe, 1998; Jones et al., 2006).Estrogen Mimics – Essay Example. This includes the brain, where estrogen may act via its classic nuclear receptors, which are widely distributed in the brains of males as well as females, or via rapid membrane actions (Toran-Allerand, 2005; Balthazart and Ball, 2006; Brann et al., 2007; Micevych and Dominguez, 2009).
Today estrogens remain the recommended active compound for the short-term treatment for menopausal symptoms (American College of Obstetricians and Gynecologists Women’s Health Care Physicians, 2004), but links to cancer (especially breast and uterus) and the unexpected finding that current HRT regimes exacerbated rather than ameliorated susceptibility to stroke and heart attacks in postmenopausal women (Rossouw et al., 2002; Murphy et al., 2003; Wise et al., 2009) led to a precipitous fall in the rate of prescribing estrogen-based replacement therapies (Mandavilli, 2006; Lewis, 2009). However, this shock has stimulated a heightened interest in the extraordinary, cell-specific nature of the effects of estrogen, its metabolites and natural isomers in diverse tissues throughout the body. In particular, research into the actions of estrogen in the brain alone has produced an average of almost two publications a day for the last couple of years. These document the profound effects and multiple mechanisms of action of estrogen on memory, mood, mental state, and neurodevelopmental and neurodegenerative processes, providing mounting support for the views that estrogen is neurotrophic, neuroprotective, and psychoprotective (Fink et al., 1996; McEwen and Alves, 1999; Gillies et al., 2004; Craig et al., 2005, 2008; Cahill, 2006; Brann et al., 2007; Craig and Murphy, 2007a,b). Estrogen-based therapies therefore hold enormous promise for brain disorders that affect both men and women (Rochira et al., 2002; Jones et al., 2006). However, the overwhelming proportion of experimental investigations of estrogen effects in the brain have been performed in females, which contrasts starkly with the majority of basic neuroscience research that uses males (Cahill, 2006; Luine, 2007).
There is now a growing literature to suggest that, in addition to similarities between male and female brains, there are marked sex dimorphisms in brain morphology, neurochemistry, hard-wiring, and functional outcomes (De Vries and Boyle, 1998; Simerly, 2005; Cahill, 2006; Cosgrove et al., 2007). Moreover, increasing evidence suggests that estrogen can have different (sometimes opposite) effects as well as similar effects in male and female subjects, probably because of underlying brain dimorphisms that occur in some brain processes but not others.Estrogen Mimics – Essay Example. These observations come from diverse areas of the literature ranging from neuroscience and neurodegeneration to cognitive and reproductive behaviors. Therefore, the purposes of this review are as follows:
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to assimilate evidence from some major brain areas, such as the hypothalamus, midbrain, hippocampus, and prefrontal cortex.
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to document sex dimorphisms in the neural substrate in experimental species and humans, where it is known.
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to analyze evidence that estrogen plays important roles in the male as well as female brain, with a particular focus on studies involving both male and female subjects in which the actions of estrogen have been directly compared.
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to question the origin of these differences (arising developmentally or in adulthood), which has great significance for understanding the foundations of sex differences in the prevalence, progression, and/or severity of many of the common neuropsychiatric and neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, drug addiction, and schizophrenia.
These discussions constitute a strong argument for the urgent need for a better understanding of brain sex dimorphisms, as well as sex-specific responses to estrogen/estrogen mimics. Such knowledge of the physiological and pharmacological relevance of estrogen actions in the brain is essential if we are to realize the full translational potential of this ubiquitous steroid for promoting human health and wellbeing. Furthermore, it will highlight the importance of adopting a sex-specific approach to treating highly debilitating neurological and neuropsychiatric conditions, the prevalence of which is increasing (Szpir, 2006; Becker and Hu, 2008; Mayes et al., 2008; Williams et al., 2008). Estrogen Mimics – Essay Example.
II. Definitions, Concepts, and Why Brain Sex Dimorphisms Are Important
Throughout this article, the term sex will be used to distinguish male or female subjects according to the reproductive organs and functions that derive from the chromosomal complement (individual organisms bearing the male XY or female XX sex chromosomes seen in most mammals). This is distinct from the term gender, used to refer to a human subject’s self-representation as male or female (Wizeman and Pardue, 2001). In addition, although male and female are traditionally used only as adjectives, they will sometimes be used as nouns to avoid convoluted language.
There are hundreds, if not thousands, of original articles in the scientific literature that address topics that pertain to this review. Therefore, we shall refer wherever possible to many excellent reviews by experts in their fields, rather than the original manuscripts, which would be too copious. Estrogen Mimics – Essay Example.
A. Sex Dimorphisms Are Widespread in Animal and Human Brains and Are Not Restricted Only to Reproductive Functions
For several decades it was a generally held belief that differences in male and female brains were the sole privilege of the hypothalamus, the brain region regulating the production of reproductive hormones and mating behaviors in all mammalian species. Early evidence for sex differences in learning and cognition (Carey, 1958) were largely attributed to environmental and sociocultural factors. However, the last decade has seen an exponential increase in evidence for structural, cellular, and molecular sex differences in the brain that can be described as true dimorphisms, defined as the occurrence of two forms in the same species. These include regions of human and animal brains that are important for cognition, memory, and affect, such as the hippocampus, amygdala, and cortex (Kelly et al., 1999; Baron-Cohen et al., 2005; McCarthy and Konkle, 2005; Cahill, 2006; Cosgrove et al., 2007; Wilson and Davies, 2007), and for regions controlling sensorimotor and reward systems (Becker, 1999; Dewing et al., 2006; Cantuti-Castelvetri et al., 2007; McArthur et al., 2007a). Indeed, post mortem studies, as well as evidence from new technologies for in vivo imaging, are adding rapidly to the view that sex differences in the human brain may be the norm rather than the exception (Madeira and Lieberman, 1995; Allen et al., 2003; Kruijver et al., 2003; Swaab et al., 2003; Luders et al., 2004; Mechelli et al., 2005; Cosgrove et al., 2007; Ishunina and Swaab, 2008; Swaab, 2008). Estrogen Mimics – Essay Example.
B. Origins of Sex Differences and Dimorphisms: Activational versus Organizational Effects and Hormonal versus Genetic Influences
1. Activational versus Organizational Effects.
The predominant circulating gonadal sex steroid hormones after puberty are estrogens in females and testosterone in males. Thus, sex differences in a biological response could be the result of differences in the prevailing levels of gonadal hormones in adulthood, with no presumptive sex differences in the underlying biological substrate. For example, in humans and in species used in research, administration of androgens to females may induce aspects of male-typical behavior that revert to normal once hormone treatment ceases; the cyclical rise and fall in levels of ovarian hormones in women and animal species used in research also influences many behaviors (Kelly et al., 1999; Halpern and Tan, 2001; Cahill, 2006; Goldstein, 2006; Wilson and Davies, 2007). These are traditionally called activational (reversible) effects (Arnold and Breedlove, 1985; Williams, 1986) or hormonally modulated responses (McCarthy and Konkle, 2005), which dictate sex differences at molecular, cellular, and functional levels but are not in themselves true dimorphisms. However, not all features of adult brain activity that exhibit sex differences are trans-sexual; that is, they cannot be equalized if an equivalent hormonal environment is created experimentally in both sexes by the administration of sex hormones to gonadectomized animals. Estrogen treatment of adult castrated rats cannot feminize all male CNS functions and androgen treatment of adult ovariectomized rats cannot masculinize all aspects of female CNS function because of permanent (irreversible) sex-specific organization of the brain during development (see also section IV). The classic concept of sexual differentiation of the brain, originating from work on the hypothalamus, states that once formation of the fetal testes is established by the Sry gene (sex determining region of the Y chromosome), sexual differentiation of the brain is a hormone-dependent process (Arnold and Gorski, 1984; Morris et al., 2004; Simerly, 2005; McCarthy, 2008). The key factor is the masculinizing/defeminizing effect of testosterone, produced by a transitory activation of the testes during a critical developmental window, lasting from the late embryonic period to the first week of life in rats (Huhtaniemi, 1994) (Fig. 1A). Testosterone freely enters the brain and, perhaps surprisingly, in certain regions its ability to sculpt the male brain relies principally on its conversion to estradiol by local aromatase enzymes. Estrogen receptor (ER)-dependent influences on processes such as neurogenesis, apoptosis, and migration then ensue to imprint enduring sex differences in the number of cells and their distribution within specific regions or nuclei. Estrogen Mimics – Essay Example. In addition, influences on neurite extension/branching, synaptogenesis, and establishment of neurochemical phenotype establish sex differences in projection pathways, innervation density, connectivity, and neurotransmitter control in specific brain regions (Simerly, 1989; De Vries and Simerly, 2002; Simerly, 2005; Wilson and Davies, 2007; Forger, 2009; Tobet et al., 2009). In addition to producing sex dimorphisms in the “hard-wiring,” perinatal exposure to testosterone (after aromatization) can also program sexually dimorphic patterns in ER expression in selected adult brain regions, which can have profound effects on the way a cell or pathway responds to estradiol (see sections III and IV and Table 1). Many advances have been made recently in the cellular and molecular mechanisms by which testosterone/estradiol engenders a sexually differentiated brain, and both classic nuclear and non-nuclear mechanisms that are active in the adult brain play a role. These are thoroughly reviewed elsewhere (McCarthy and Konkle, 2005; Wilson and Davies, 2007; McCarthy, 2008) and are of particular interest not only for understanding the actions of estrogens in the developing brain but also for possibly providing clues about estrogenic actions in the injured brain, in which certain developmental processes may be recapitulated in attempts to protect, repair, and recover.
Patterns of hormone exposure throughout life: a biological basis for sex differences in the brain. In male rats (A) and humans (C), a transitory activation of the testes during a critical developmental window means that the brain develops in a different hormonal environment in males and females, which establishes irreversible sex dimorphisms in specific neural circuits. After puberty, the rise in gonadal steroids in males and females activates the sexually dimorphic circuitry; the rodent (A) and human (C) male brain is exposed to a relatively steady level of the main gonadal steroid, testosterone, for most of adult life. In contrast, the rodent (B) and human (D) female brain is exposed to a cyclical pattern of the main gonadal steroid, estradiol, for a certain period of adult life, until levels fall precipitously at reproductive senescence or menopause.Estrogen Mimics – Essay Example.
TABLE 1
Summary of the major findings on ER distribution in the adult brain
The diversity of approaches taken when investigating ER distribution in the brain are illustrated. Some studies present data throughout the brain, whereas others focus on specific areas, with variations in the use of intact and gonadectomized rodents and the sex of the subjects under investigation. Along with difficulties inherent in the absolute quantification of immunoreactivity (IR) and in situ hybridization (ISH) signals, this complicates direct comparisons between studies. Overall, however, there is a strong consistency for the anatomical organization of ERs in the brain: it is clear that across species, ERα and ERβ are widely distributed in brain regions that are and are not principally associated with reproductive functions. Although overlapping in many brain regions, ERα and ERβ have distinct patterns of distribution. In humans and rodents, the hypothalamus (especially the VMN) and amygdala emerge as ERα-dominant regions (Shughrue et al., 1997; Osterlund et al., 2000a,c), providing neuroanatomical evidence for a role in regulating neuroendocrine, autonomic, emotional, affective, and motivational responses. Both ERα and ERβ are found in the hippocampus in rodents and humans, ERβ being the dominant form in the human subiculum (where information leaves the hippocampus to influence amygdala, cortical, and subcortical structures). ERs are thus well placed to influence learning and memory. The basal ganglia are notable by their relative lack of classical ERs. The distribution patterns of ERs are remarkably similar in adult male and female brains. However, sex differences are present in the relative levels of expression in hypothalamic subnuclei involved in reproductive processes, which may be determined early in life (Khünemann et al., 1994; Orikasa et al., 2002; Ikeda et al., 2003).Estrogen Mimics – Essay Example. In the human hypothalamus, sex differences were also revealed by closer analysis of their subcellular distribution to the nucleus, cytoplasm, and nerve terminals (Kruijver et al., 2002). In contrast, a lack of overall sex differences in ER expression levels was notable in the hippocampal regions, where estradiol-responsiveness is known to be sexually dimorphic (Weiland et al., 1997). Sex differences are also absent in the cortex (Kritzer, 2002), but finer analysis revealed that males and females did exhibit differences in the cytoarchitectural localization of ERs in the mesocortical neurons supplying different regions of the PFC (Kritzer and Creutz, 2008). Estrogen Mimics – Essay Example.
