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Department of Biosciences and Medical Nutrition, Novum, Karolinska Institute, Karolinska University Hospital, Huddinge, SE-141 86 Sweden
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONESTROGEN IN THE CENTRAL...ERß AND PROSTATIC...REFERENCES |
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estradiol, estradiol receptor, immunology, neurotransmitters, prostate
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONESTROGEN IN THE CENTRAL...ERß AND PROSTATIC...REFERENCES |
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) and ERß, has been instrumental in our understanding of how estrogen exerts its various physiological and sometimes opposing effects [2]. After having cloned ERß, we focused on unraveling the function of this receptor. Because estrogen signaling is a dynamic balance between ER and ERß [3], our group is investigating both ERs. Estrogen and the Immune System Autoimmunity: A Major Women's Health Issue
Autoimmunity is the underlying cause of more than 100 serious, chronic illnesses [4, 5]. Autoimmune diseases strike women primarily, with some occurring 10 times more frequently in women than in men [6]. More women than men are affected by autoimmune diseases such as Sjögren syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis. Despite these statistics, autoimmune diseases remain poorly understood. To help women live longer and healthier lives, a better understanding of the diseases is needed, as well as better, more effective methods of diagnosis and treatment, because a majority of the treatment modalities are symptomatic [7].
To gain a better understanding of why women have a higher risk for autoimmunity, estradiol (E2) has been under intense scrutiny. The precise role of E2 in autoimmunity has never been understood, primarily because E2 has contradictory effects on the immune system. Although it appears to offer protection against end-stage renal disease, during the development of SLE, E2 blocks the destruction of immature autoreactive B cells in the bone marrow of mice and promotes autoimmunity [8]. Furthermore, treatment of lupus-prone mice with E2 increases the incidence of autoimmune disease [9, 10], whereas tamoxifen, an ER antagonist, seems to suppress SLE [11]. With the exception of estrogen treatment of neonatal (NZB x NZW F1) mice [12], it is generally widely accepted that E2 aggravates lupus nephritis. In direct contrast, E2 can suppress the development of the autoimmune exocrinopathy Sjögren syndrome [13], and ovariectomy mimics Sjögren syndrome in mice of healthy backgrounds [14]. It is our working hypothesis that the different effects of E2 are mediated by its interaction with the two ERs, ER and ERß. The net effect of E2 is determined by a balance between ER and ERß within different cells of the immune system [15]. In the total absence of E2, the immune system is different from both the ER-deficient and the ERß-deficient system [16]. Therapeutic effects of ER, ERß, and their selective agonists and antagonists on different autoimmune diseases are being further investigated.
Estrogen Receptors in the Regulation of Autoimmune Diseases
So far, we have investigated three different genetic models of estrogen deficiency to better understand the contradictory effects of estrogen in autoimmune diseases [15–17]. Thus, aromatase knockout mice (i.e., cytochrome P450, family 19, subfamily a, polypeptide 1: Cyp19a1–/–) [16], Er–/– mice [17], and Erß–/– mice [15] show three distinct immune disorders, respectively. Autoimmune nephritis was found in Er–/– mice [17], myeloid leukemia in Erß–/– mice [15], and spontaneous development of Sjögren syndrome without preconditioning in Cyp19a1–/– mice [16]. These results suggest that selective antagonists and agonists of ERs have the potential to treat and, perhaps cure, diseases of the immune system if the drug is carefully chosen according to the symptoms of the disease.
ERß in Chronic Myeloid Leukemia
Recently, we found and published results that inactivation of the Erß gene in mice leads to a chronic myeloid leukemia-like syndrome [15]. In this study, a novel role for ERß in regulating the differentiation of pluripotent hematopoietic progenitor cells was demonstrated. These results suggest that the Erß–/– mouse is a potential model for myeloid and lymphoid leukemia, and that ERß agonists might have clinical value in the treatment of leukemia if the Erß is not itself mutated in this disease. The human Erß gene has been mapped to chromosome 14q22 [18]. Hairy cell leukemia shows, interestingly, underexpression of 14q22– 24 [19]. Authors suggest that these regions contain genes related to the biology of hairy cell leukemia.
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ESTROGEN IN THE CENTRAL NERVOUS SYSTEM |
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TOPABSTRACTINTRODUCTIONESTROGEN IN THE CENTRAL...ERß AND PROSTATIC...REFERENCES |
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In addition to its influences on development, plasticity, and survival of neurons, estrogen has effects on several neurotransmitter systems in the brain. It is an important regulator of serotonergic, dopaminergic, and cholinergic neurons [20–22].
ER is the predominant receptor subtype in the basal forebrain cholinergic neurons of the adult rat brain, where it is believed to enhance cognitive functions by modulating the production of acetylcholine [23]. Epidemiological studies suggest that estrogen replacement therapy decreases the likelihood of developing Alzheimer disease, but replacement of estrogen in older women has no effect on incidence or progression of Alzheimer disease [24–27]. This probably means that the value of estrogen replacement lies in its prevention or slowing of neurodegenerative processes and not in reversing neurodegeneration.
In the anterior dorsal raphe nucleus, E2 increases the amount of the serotonin receptor (Htr2a) mRNA and the serotonin transporter mRNA [21]. ERß but not ER is expressed in serotonergic neurons in the dorsal raphe nucleus of the mouse [28, 29]. There are still some questions about species differences in ERß expression in the dorsal raphe nucleus. The rat appears to be different from the mouse in that there is no ERß in the rat dorsal raphe [30]. However, ERß is the receptor responsible for serotonergic neurotransmission in primates [31]. In cynomolgus monkeys, phytoestrogen from soy, which is relatively selective for ERß, improves mood and enhances serotonergic transmission in the dorsal raphe [32]. It is therefore possible that a new generation of antidepressant drugs will be developed based on their ERß agonistic activity in the dorsal raphe.
The dopaminergic system is also estrogen-responsive, and estrogen can prevent or modulate insults to dopaminergic neurons [33, 34]. Parkinson disease is a progressive loss of the dopamine-producing neurons of the substantia nigra, and this causes progressive impairment of the ability of the brain to control movement [35]. In addition to movement disorders, patients with Parkinson disease suffer from defective autonomic function, cognition, behavior, and mood [36]. More that 30% of patients with Parkinson disease develop dementia [37]. Parkinson disease is more prevalent in men than in women by an approximate 3:2 ratio [38, 39], and epidemiological evidence suggests that estrogen influences the onset and severity of disease-associated symptoms [40]. Estrogen deficiency after menopause may explain why there is a high incidence of late-onset neuropsychiatric disorders in women. Recent investigations have demonstrated that estrogen administration is beneficial for the symptoms of Parkinson disease and also may have beneficial effects on cognition in postmenopausal patients and may delay or prevent the onset of dementia [41–43].
How Do Estrogens Affect Dopaminergic Pathways?
The predominant ER in neurons in the substantia nigra is ERß [29, 44], and our own studies with Erß–/– mice have shown that neuronal survival throughout life is compromised so that, by 2 yr of age, there is a remarkable amount of neurodegeneration, particularly in the substantia nigra [45].
Estrogens increase dopamine synthesis in the substantia nigra (presynaptic effects), and release of dopamine from nigral axon terminates within the striatum (postsynaptic effects). In rodents and in neuronal cell culture studies, estrogens have been shown to protect dopaminergic neurons from injury [46–50]. In monkeys, more than 30% of nigral dopaminergic neurons are lost 30 days after ovariectomy [51]. This loss can be prevented by estrogen supplementation within 10 days of ovariectomy. At later time points, the loss is permanent and estrogen cannot restore the neurons. Thus, as in the case with cholinergic neurons, estrogen may be necessary for the maintenance and survival of dopaminergic neurons, but it cannot replace neurons that have been lost. All of this means that therapeutic intervention must be aimed at prevention of neurotoxicity. The cause of dopaminergic cell death in Parkinson disease is still unknown, but Parkinson-like diseases can be induced in animals and humans by neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which destroy neurons in the substantia nigra [52]. At least some of the sensitivity of the neurons of the substantia nigra to neurotoxins is the presence in these cells of neuromelanin, a substrate that generates reactive oxygen species. Estrogen is also reported to protect dopaminergic neurons from MPTP and other toxins, and from oxidative stress [51].
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ERß AND PROSTATIC DISEASE |
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TOPABSTRACTINTRODUCTIONESTROGEN IN THE CENTRAL...ERß AND PROSTATIC...REFERENCES |
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Studies of Erß–/– mice [53] revealed an ERß role in many tissues and organs, including the ovary, uterus, mammary gland, brain, immune system, and prostate [2]. Both ER and ERß are expressed in some tissues, and the specific function of each receptor is sometimes difficult to evaluate, particularly in cases in which the two receptors oppose the action of each other [54]. The strong influence of estrogen on the central nervous system-gonadal axis is a further confounding factor that makes it hard to distinguish direct ERß-mediated and indirect systemic influence of changes in the hormonal environment [55]. The epithelium of the adult mouse ventral prostate expresses high levels of ERß (but not ER) [1]. ER is expressed in the stroma [56–62]. Thus it is likely that a direct estrogenic influence exists on adult prostatic epithelium mediated by ERß.
Treatment of Erß–/– mice with diethylstylbestrol (DES) results in hyperplasia similar to that in wild-type mice, but Er–/– mice are resistant to imprinting by neonatal DES [63]. These data suggested that ER mediates the effects of neonatal estrogens on the prostate. In the adult rodent ventral prostate, ERß is the only ER expressed in the epithelium, whereas ER is expressed in the stroma [64]. Thus, it was initially believed that estrogen acts on stromal ER to stimulate growth factor release, and that these growth factors caused epithelial proliferation [63, 65]. In a set of experiments performed in our laboratory, we showed that in the ventral prostate epithelium of mice, ER is highly expressed in the first 3 wk of the postnatal period. Between Weeks 2 and 4, the ventral prostate epithelium switches from an ER-dominant, highly proliferative tissue to an ERß-dominant, differentiating tissue. This switching of ERs marking the end of proliferation/growth and the beginning of differentiation/functional activation of the prostate, and is accompanied by changes in expression of androgen receptor (AR). This notable ER switch marks the change in the tissue behavior occurring under an unchanging hormonal environment, and is a good example of opposing actions of ER and ERß, best described by the ancient Chinese Yin-Yang paradigm.
We have reported that loss of ERß results in epithelial hypercellularity in the ventral prostate [66, 67], but this description has not met with consensus in all laboratories [53, 67, 68]. However, absence of estrogen, as is found in the Cyp19a1–/– mouse, leads to epithelial hyperplasia in the ventral prostate [69]. It has been shown that transgenic mice that overexpress AR exhibit prostate epithelial hyperplasia [70], and we have shown that lack of ERß leads to up-regulation of the AR in the ovary, prostate, and brain [71]. To clarify the cause of the epithelial hyperplasia observed in our Erß–/– mice, we have compared the ventral prostates of wild-type and Erß–/– mice, measured proliferation rates, apoptosis markers, and characterized differentiation pattern of the Erß–/– mouse ventral prostate.
We have found overexpression of the antiapoptotic factor BCL2 in ventral prostates of Erß–/– mice [72]. Bcl2 is an estrogen-regulated gene [73]. It is normally expressed only in the basal cell layer of the prostate, a possible localization of progenitor cells [74, 75]. There is also a higher expression of cytokeratin 5 in Erß–/– mouse prostates so that the ratio of cytokeratin 5 to that of 19 is much higher in Erß–/– than in wild-type littermates, suggesting an altered differentiation pattern of Erß–/– ventral prostate epithelium [72]. In the same article we reported that labeling of DNA with bromodeoxyuridine showed a 3.5-fold higher proliferation rate in Erß–/– mouse prostates. Despite these clear differences, the piling up of epithelial cells never progressed to high-grade prostatic epithelial neoplasia (PIN) lesions, a known precursor of prostate adenocarcinoma [76, 77]. Hyperplastic foci in Erß–/– mice show accumulation of cells without signs of atypia, resembling low-grade PIN in humans. The reason for this seems to be a high rate of cellular detachment and subsequent fall off into the lumen in Erß–/– mice. The fall-off phenomenon is possibly related to the altered expression of the cell adhesion molecules.
Our working hypothesis is that the epithelial cell lineage of the prostate developing in the absence of ERß signaling is altered. In Erß–/– mouse ventral prostates the epithelial cell population seems to contain more cells in the intermediate stages of differentiation, possessing the ability to rapidly proliferate upon androgen stimulation [78].
Our data suggest a prodifferentiation role of ERß in prostatic epithelium [72]. This means that selective ERß ligands could be useful in a neoadjuvant and possibly even preventive therapy for prostate adenocarcinoma. ERß-selective agonists could shift a tumor to a higher differentiation grade, thus bringing the tumor to a less malignant behavior and improve overall prognosis.
As a support to our findings came the surprising results from the Prostate Cancer Prevention Trial (PCPT), which caused lively discussion in the literature [79–81]. The results of the study, we believe, can be explained in the context of our findings. More than 18 000 healthy volunteers aged 55 or older were randomized into two study arms: finasteride 5 mg daily and placebo, respectively. Being promising and hopeful at the beginning, the study resulted in rather intriguing results. The incidence of prostate cancer in the finasteride arm was 18.4% vs. 24.4% in the placebo arm. The biggest surprise, however, came from the finding that in the finasteride-treated group, the incidence of Gleason 7–10 tumors was 67% higher, a fact that would alarm any urologist [79–81].
Including ERß into the hypothetic scheme of endocrinological control of prostate would give us the following:
Thus, the prostatic epithelial cell that proliferates under AR influence stops and differentiates into a mature secreting cell under ERß influence. Because proliferation and differentiation processes oppose each other, one should consider the existence of a dynamic balancing mechanism in the system. However, until recently, the search for such a mechanism was lacking a key component: the natural ligand for ERß.
Several publications showed that phytoestrogenic compounds, such as genistein, show higher affinity to and stronger activation of ERß [82, 83]. Moreover, genistein reduces the incidence of poorly differentiated prostate cancers in transgenic mice [84]. One may speculate that the protective role of phytoestrogens against prostate cancer [85, 86] is mediated via ERß.
Investigations of ERß in our laboratories showed that a steroidal compound, 5-androstane-3ß,17ß-diol (3ß-androstanediol), located downstream of reduction of testosterone (T) to 5-dihydrotestosterone (DHT) by SRD5a2, shows all characteristics of the natural ligand for ERß [87]. The balance between proliferation and differentiation in the prostatic epithelium is probably maintained by enzymes HSD17B3 and CYP7B1. The gentle equilibrium between the activities of these enzymes programs each prostatic epithelial cell to either proliferation or differentiation.
The presented pathway also provides a possible scenario of long-term finasteride treatment. Blocking T-DHT reduction by SRD5a2 blocking agents, like finasteride, also blocks downstream production of 3ß-androstanediol, thus suppressing ERß action, and altering the normal differentiation of prostatic epithelium. The initially beneficial process of AR suppression runs into the dilemma of blocking ERß.
We believe that a higher incidence of low-differentiated tumors in the finasteride-treated arm observed in the PCPT is caused by altering the normal differentiation of prostatic epithelium in the environment lacking the natural ERß ligand—3ß-androstanediol.
From a pharmacological point of view, blocking SRD5a2 activity and altering the T-DHT pathway has obvious benefits that have been discussed elsewhere. However, the downstream consequences of such biochemical intervention consists in withdrawal of steroidal compounds lying along the T pathway. One of them, 3ß-androstanediol, serves as a natural ligand for ERß and promotes differentiation of prostatic epithelium.
ERß Selective Ligands
We know that ER is the dominant receptor in the adult uterus, and this is why loss of ERß does not affect the response of the uterus to estradiol [88]. ERß is expressed at high levels in other estrogen-target tissues such as the prostate, salivary glands, ovary, vascular endothelium, smooth muscle, certain neurons in the central and peripheral nervous systems, and the immune system [2]. In these tissues, which depend on estradiol for maintenance of structure, function, or both, estrogenic signals are mediated by ERß. In cell lines [89] and in some tissues [67, 90], E2 in the presence of ER elicits proliferation, but in the presence of ERß it inhibits proliferation; one and the same hormone, two opposite effects.
The standard test for an estrogen, stimulation of growth of the uterus, is of course, still a good test for an ER agonist, but there is no single good test for an ERß agonist. In fact, there may not be such a thing as a single good ERß agonist. What is emerging is an array of ERß-selective agonists, each with a specific profile of genes, that they influence [91–96]. Although we know what a consensus estrogen-response element (ERE) is, most estrogen-responsive genes do not contain perfect consensus sequences and the transcriptional activity of ER or ERß on such sequences is influenced by the chemical structure of the estrogenic ligand. Hall and Korach [97] have evaluated the activities ER and ERß on four different EREs (vitellogenin A2, human pS2, lactoferrin, and complement 3) in the presence of estradiol, phytoestrogens, and xenoestrogens. In terms of transactivation by ER and ERß, the vitellogenin and lactoferrin promoters were not discriminatory. The pS2 and complement 3 were most responsive to ERß but very weakly to ER. In addition, the transcriptional activity of either receptor on any promoter varied with the ligand.
Another factor influencing selectivity of ER ligands is that the influence of estrogen receptors on transcription is not confined to EREs. Estrogen receptors modulate transcription at AP-1 and Sp1 sites and interact with the nuclear factor 
B pathway [98]. The action of the two receptors at these sites can be opposite to each other, but this depends on cellular context and it is not possible to predict how ER and ERß will influence transcription at these sites. Selective ER and ERß ligands have already been developed that have actions on selective target tissues and even selective target genes [99]. One ERß agonist developed by Eli Lilly is a great inhibitor of prostate growth but has no effect on the immune system [100], while one developed by Wyeth is a powerful immune suppressant but has no influence on the prostate [92].
In summarizing the accumulated knowledge on estrogen signaling in various organs one can expect a paradigm change in the medical treatment of different hormone-dependent diseases while an array of other diseases has yet to be elucidated.
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FOOTNOTES |
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2 Correspondence. FAX: 46 8 779 87 95; jan-ake.gustafsson{at}mednut.ki.se
Received: 3 May 2005.
First decision: 2 June 2005.
Accepted: 15 July 2005.
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TOPABSTRACTINTRODUCTIONESTROGEN IN THE CENTRAL...ERß AND PROSTATIC...REFERENCES |
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