Jan-Åke Gustafsson

Estrogen Receptor beta in Health and Disease

Abstract Estrogens, acting through its two receptors, ESR1 (hereafter designated ER alpha) and ESR2 (hereafter designated ER beta), have diverse physiological effects in the reproductive system, bone, cardiovascular system, hematopoiesis, and central and peripheral nervous systems. Mice with inactivated ER alpha, ER beta, or both show a number of interesting phenotypes, including incompletely differentiated epithelium in tissues under steroidal control (prostate, ovary, mammary, and salivary glands) and defective ovulation reminiscent of polycystic ovarian syndrome in humans (in ER beta−/− mice), and obesity, insulin resistance, and complete infertility (both in male and female ER alpha−/− mice). Estrogen agonists and antagonists are frequently prescribed drugs with indications that include postmenopausal syndrome (agonists) and breast cancer (antagonists). Because the two estrogen receptors (ERs) have different physiological functions and have ligand binding pockets that differ enough to be selective in their ligand binding, opportunities now exist for development of novel ER subtype-specific selective-ER modulators.

Estrogen receptors do not influence angiogenesis after myocardial infarction.

Abstract Background. There is controversy on whether estrogen receptors are present and functioning in the myocardium. Aims. To explore if after myocardial infarction (MI) estrogen receptors α (ERα) and β (ERβ) are upregulated in myocardial tissue and to explore if the presence/ absence of ERα or ERβ influences angiogenesis after MI. Methods. MI was induced by ligation of the left anterior descending artery in knockout (KO) mice, ERαKO and ERβKO, respectively, and non-KO littermate-controls, C57Bl/6 mice. The hearts were harvested after 12 days. A part of the periinfarct tissue was collected for ERα and ERβ mRNA expression determination by real-time polymerase chain reaction. Using immunohistochemistry, ERα and ERβ protein expression and capillary and arteriolar densities were blindly determined in the periinfarct area. Results. In myocardium disrupted mRNA was upregulated in both ERαKO and ERβKO, (p < 0.005) and did not change after MI. There was no change in mRNA expression of ERα or ERβ in wild type mice after MI. Expression of ERβ in ERαKO and of ERα in ERβKO did not change. Following MI ERα or ERβ could not be demonstrated by immunohistochemistry in either wild type or ERαKO or ERβKO. The capillary and arteriolar densities after MI did not differ between the groups in the periinfarct area. Conclusions. Although disrupted ER mRNA is upregulated in myocardium of ER knockout mice, no change in these or native receptors occurs following MI. At least in this model ER therefore seems not to have a role in myocardial arteriogenesis and angiogenesis after MI.

Cytochrome P450 in the Central Nervous System

The brain is a major target for the action of steroids. These molecules regulate many aspects of brain function, including imprinting of sexual behavior (1), learning and memory (2), and mood and sleep/wakefulness (3). They are also thought to modulate neurodegenerative processes (4,5). The brain is, of course, also the target of many pharmaceutical agents, fatty acid metabolites, and organic solvents. Synthesis and degradation of steroid hormones, as well as the activation and inactivation of therapeutic agents and fatty acids involve several members of the cytochrome P450 super gene family (6,7). P450s are abundant in the adrenals, gonads, and liver, however, when measurable, most P450s are expressed at very low levels in the brain (8). The capacity of the brain to metabolize pharmaceuticals is so low that it is most unlikely that P450 in the brain plays any role in the overall clearance of pharmaceuticals from the body. However, those P450s that are selectively localized at high concentrations in limited numbers of brain cells, can play important roles in the physiology, pharmacology, and toxicology of those cells.

Structure and Function of the Estrogen Receptor

The two estrogen receptors (ER), α and β, belong to the steroid/thyroid hormone receptor family of ligand-dependent transcription factors. Through interaction between distinct domains of the ERs with natural and synthetic ligands, with various proteins and with DNA, they can modulate the activity of target genes and a number of other processes within the cell. We review in this chapter the domains of ERα and ERβ and their functional differences and role in ER biology, as well as what we know today about the different mechanisms of ER-dependent target gene regulation.

3.03 – Genetic and Epigenetic Mechanisms in Neural and Hormonal Controls over Female Reproductive Behaviors

Building on well-established mechanisms that produce the primary female mating behavior, lordosis, research is extending into mechanisms for sexual arousal. Genes and neurochemical pathways supporting sexual arousal are reviewed, and four neurochemical/biophysical routes by which generalized arousal could influence sexual arousal are charted.

Three Nuclear Receptors Involved in Gender-Related Proliferative Diseases (ER-β LXR-α, and LXR-β)

There are some diseases like autoimmune diseases, osteoporosis, and lymphangioleiomyomatosis where estrogen, the predominant female hormone, could play an important role. Despite major advances in med