Genomic Effects:
The classical genomic actions of sex hormones are mediated by their receptors that act as ligand-activated transcription factors. As soon as the sex hormone is integrated into the cell, it binds to the ligand-binding domain of the receptor, resulting in the dissociation of the receptor from its cytoplasmic chaperones. This consequently, after nuclear transloaction, leads to the formation of a homodimer or a heterodimer. This formation of the hormone-receptor complex binds to the hormone response elements located on the promoter or enhancer regions of target genes. The direct or indirect binding of the homo/hetero dimer is configured by how the complex interacts with other transcription factors such as the activator protein (AF-1) , specificity protein 1 (SP-1), or transcriptional factors ( such as co-activators, co-repressors) that ease the modulation of transcription In addition, NF-kB (as introduced before as the regulatory mechanism involved in the ERα expression) interaction with ER has been shown to "mediate E2-dependent transcriptional regulation of genes that lack estrogen response elements." (The involvement of E2 has resulted in the regulation of gene transcription in cardiac tissue and cells in a sex-specific manner. For example, "E2 induces female-specific increase in progesterone receptor levels, which might confer females protection." Moreover, "E2 induces a male specific increase myosin regulatory light-chain interacting protein (MYLIP), which leads to reduced contractility in males." ( Regitz-Zagrosek and Kararigas, 2017)
Non-Genomic Factors:
Recently, most studies on cardiovascular disease have focused on non-genomic actions of sex hormones.
Non-genomic actions of sex hormones are "rapid and mediated by classic receptors located in or adjacent to the plasma membrane or by other plasma membrane bound receptors."( Drevenšek, 2012). Due to the rapid changes of non-genomic factors, phenotypical changes occur almost immediately after exposure to sex hormones and affect signalling pathways.
In the article, "The Role of Sex Hormones in Cardiovasular Disease," the authors found that "estrogens in premenopausal women with regular menstrual cycle are established as a natural protection against cardiovascular diseases through nuclear and non-nuclear mechanisms. (Drevenšek , 2012).
The non-nuclear process of estrogen is attributed to their direct "vascular effects and antioxidative activity."
The authors presented a new pathway discovered in the last years showing that the "plasma membrane G protein estrogen receptor (GPER1) is involved in cardioprotection of both in females as in males." (Drevenšek , 2012).
Another article proposed that "even though studies have shown that premenopausal women having a low incidence of cardiovascular disease as compared to men, the mortality among post-menopausal women rises to the same frequency or even exceeds the rates of men." (Drevenšek, 2012)
At the nuclear level, the non-genomic activities of estrogen includes the the activation of extracellular signal-regulated kinase 1 and 2 (ERK 1/2) and src, and the increased phosphorylation of c-jun-NH2- terminal protein kinase. In the myocyte, estrogen"modulates signals through phosphoinositide 3-kinase (P13K), PKB, glycogen synthase kinase 3β (GSK3β), β-catenin, calcineurin, mechanistic target of rapamycin, mTOR, ERK 1/2, p38, MAPK, and JNK." ( Regitz-Zagrosek and Kararigas, 2017).
Therefore, the involvement of estrogen in the nuclear level , demonstrates that estrogen is involved in various cytoplasmic signaling pathways through non-genomic actions.
Toxicology: testosterone and non-genomic effects
Testosterone, being the most important natural androgen in the body, produces a very active metabolite, DHT, which binds very strongly to the AR (androgen receptor). Studies have reported cardio-toxic effects of testosterone in the cardiovascular system mainly due to the "supra-physiological androgen abuse" which has reportedly shown an increase in LV mass and hypertrophy, causing MI and Diastolic Dysfunction. In recent studies, testosterone has show to express significant cardio protection in "diminished reperfusion injuries, decrease arrhythmias. Therefore, testosterone must possess non-nuclear activity at the cytoplasmic level similar to that of estrogen.
References
1. Gorazd Drevenšek (2012). The Role of Sex Hormones in the Cardiovascular System, Sex Hormones, Prof. Raghvendra Dubey (Ed.), ISBN: 978-953-307-856-4, InTech, Available from: http://www.intechopen.com/books/sex-hormones/the-role-of-sex-hormones-in-cardiovascular-system-and-diseases-
2. Regitz-Zagrosek V, Kararigas G. Mechanistic Pathways of Sex Differences in Cardiovascular Disease. Physiol Rev. 2017 Nov;(1):1-37.