Role of nuclear and membrane estrogen signaling pathways in the male and female reproductive tract☆
Introduction
Estrogen is critical for the normal development and function of the female reproductive tract. Effects of estrogens on reproductive organs such as the uterus, mammary glands, oviduct and vagina have been the most intensively studied. However, estrogens also have critical effects on a wide variety of non-reproductive targets such as brain, adipose tissue, the vascular system, bone, thymus and other tissues (Hewitt and Korach, 2018).
Although estrogens are typically associated with female reproductive biology, estrogens have important effects on male reproductive and non-reproductive organs as well. The knockout mouse technology that has generated so many important insights into various facets of steroid hormone receptor biology has been critical for establishing estrogen actions in the normal male. Therefore, understanding the overall effects of estrogens involves elucidating their roles in male as well as female reproductive biology.
Seminal work beginning in the 1960s established that estrogen binds to specific receptor proteins in target cells, and that the estrogen-receptor complexes subsequently were located in the nucleus, where they regulate gene transcription (Jensen et al., 1967; Jensen and Jacobson, 1960; Jensen et al., 1969; O'Malley and McGuire, 1968; Toft and Gorski, 1966). These pioneering observations focused research interest on nuclear actions of estrogens and other steroid hormones. Despite the primacy of nuclear signaling for the action of estrogens and other steroids, a few reports began appearing that described rapid actions of steroids, sometimes within a few seconds, that occurred too quickly to be through the genomic nuclear pathway then being described in increasing detail.
These types of hormonal mechanisms, called non-classical or non-genomic effects to distinguish them from the classical genomic effects mediated by steroid hormones through nuclear signaling, were eventually determined to involve membrane effects induced by estrogen and other steroid hormones. This chapter traces the evolution of our understanding of the identity, location and mechanism of action of membrane receptors for estrogen, with a special emphasis on recently developed transgenic mouse model systems that have allowed the importance of this facet of steroid hormone signaling to be demonstrated in vivo.
The estrogen receptor originally identified by Jensen, Gorski and others (Jensen et al., 1967; Jensen et al., 1969; O'Malley and McGuire, 1968; Toft and Gorski, 1966) was initially thought to be the sole estrogen receptor, but it is now known as estrogen receptor 1 (ESR1) or ERα to distinguish it from a second form of estrogen receptor, now known as ESR2 or ERβ, that was described by Jan-Ake Gustaffson and colleagues in 1996 (Kuiper et al., 1996). Work described here focuses on membrane ESR1 (mESR1), which has recently been shown to play a major role in estrogen signaling. Although other functional membrane estrogen receptors also exist, a critical role for them in normal reproduction has not been demonstrated, as described in part VII of this review.
Section snippets
During sexual differentiation, pre-pubertal development and adulthood
Our basic understanding of sexual differentiation in fetal gonads and hormonal regulation of internal and external reproductive organ development was established seven decades ago by Jost and colleagues (Jost et al., 1973). Although estrogen signaling through ESR1 is critical for adult female reproductive development and function, ESR1 is dispensable for normal sexual differentiation of the fetal female reproductive tract, as shown by the Esr1 knockout (Esr1KO) mouse (Lubahn et al., 1993). Loss
Effects of E2/ESR1 signaling on the male reproductive tract
An extensive literature that extends from the early part of the 20th century to the present indicates that exogenous and endogenous estrogens have important effects on males. Measurable circulating estrogen concentrations have been reported in males from many different species (Reviewed in Cooke et al., 2017; Hess and Cooke, 2018). Estrogen receptors are widely distributed in the male reproductive tract during development and adulthood as well as in a large number of non-reproductive organs (
Estrogens produce rapid effects through receptors located in the cell membrane
Because of its roles in the male and female reproductive tract, as well as in male and female reproductive pathologies, establishing estrogen's mechanism of action has been a focus in endocrinology since estrogens were discovered independently by Doisy and Butenandt almost a century ago (Butenandt, 1929; Huffman et al., 1940; Veler et al., 1930). Early work by Elwood Jensen and collaborators established that radioactive estrogen was preferentially taken up by organs such as the uterus and
Effects of loss of membrane ESR1 on reproductive tissues in the female
Female mice in which localization of ESR1 to the membrane was inhibited but nESR1 expression was maintained have a number of reproductive abnormalities (Adlanmerini et al., 2014; Pedram et al., 2014). Although preliminary results from our laboratories indicate that these female mice may be transiently fertile in the juvenile period, the adult females are infertile and anovulatory (Table 1), with small malformed ovaries that have extensive hemorrhagic cysts and lack corpora lutea (Adlanmerini et
EZH2 expression during uterine development
The demonstration that mESR1 was critical for complete estrogen responses underlined the need to clearly understand the effects of E2 signaling through mESR1 and determine how mESR1 and nESR1 cooperate to support full estrogen signaling. Work in this area is still at an early stage, but recent studies have suggested a role of mESR1 in estrogen-induced epigenetic effects. Many studies have linked estrogen signaling with epigenetic regulation, specifically to post-translational histone
Membrane signaling is involved in the actions of many members of the steroid/thyroid hormone superfamily
Although steroid hormone membrane signaling and its importance are best understood for estrogen signaling through mESR1, this phenomenon has also been demonstrated for many other members of the steroid/thyroid hormone superfamily of receptors (Levin and Hammes, 2016). This section discusses signaling by estrogen through membrane receptors other than mESR1, and also provides an overview of an extensive literature showing membrane signaling by a number of other steroids as well as thyroid hormone.
Summary and conclusions
Rapid effects of estrogen and other steroid hormones have been reported for many decades but were initially difficult to reconcile with the model of nuclear effects of steroid hormones that emerged during the late 1960s. However, these initial observations opened the door to subsequent work that demonstrated that these rapid effects of estrogen are mediated through membrane receptors that are identical to nuclear ESR1 but localized to the membrane by a unique palmitoylation process following
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This work was supported in part by NIH grant R01 PR015540 (to P.S. Cooke and E.R. Levin).