[Lotus]

Awesome, " co-activators " such SRC-2 (steroid receptor coactivator ) enhances transcriptional activity of a variety of nuclear receptors, including ER, PR and AR (Voegel et al., 1996). Translation?....we can improve the bioavailability of hormone receptors (loosely translated)   that essentially tells the steroid receptor to behave the way WE want them too. Btw, transcription (basically) means growth.     https://en.m.wikipedia.org/wiki/Transcription_(biology)

In others words, the model i see is this......a co-administration of E2, an antihistamine or H2 receptor antagonist supplement, vitamin D, and spirolactone (or similar) should elicit SRC-2 covactivator to upregulate Estrogen Receptor Alpha, and there on to sexual differentiation (aka feminization)....the following study explains my meaning. For NBE/hrt I think this opens the door of neuro-endocrinology to new findings to stimulate sex steroids in a disease free state. 

more info see here:
Neuroactive steroids: An update of their roles in central and peripheral nervous system
https://www.researchgate.net/profile/Rob...system.pdf


Nuclear Receptor Coactivators
Abstract
The effects that steroid hormones exert on gene expression via their nuclear receptors (NRs) must be tightly regulated, in particular because of their pleiotropic effects in many tissues. To that end, regulation of receptor activity takes place at multiple levels, which include ligand availability, epigenetic modifications of chromatin around tissue-specific target genes, expression levels of the receptor, and the presence or absence of other NRs in the same cell. One of the levels of transcriptional control is that of the NR coregulators, proteins that can interact with NRs and modulate their function. Coregulators can interact with multiple NRs and NRs can interact with multiple coregulators. As a consequence, coregulator expression in certain cell types may play the roles of hubs and bottleneck that offers gene target, cell type, or context specificity. Below we offer an overview of NR coregulator function, highlighting the best-described coregulators in the brain, as well as possibilitiesfor the manipulation of NR–coregulator interactions for therapeutic or experimental purposes.



TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors.
Nuclear receptors (NRs) act as ligand-inducible transcription factors which regulate the expression of target genes upon binding to cognate response elements. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC452006/


Modulation of steroid action in the central and peripheral nervous systems by nuclear receptor coactivators

Summary Steroid hormones act in the central and peripheral nervous systems to regulate a variety of functions, including development, cell proliferation, cognition and behavior. Many of these effects of steroid hormones are mediated by their respective receptors, which are members of the nuclear receptor superfamily of transcriptional activators. A variety of cell culture studies reveal that nuclear receptor coactivators are recruited to the steroid receptor complex and are critical in modulating steroid-dependent transcription. Thus, in addition to the availability of the hormone and its receptor, the expression of nuclear receptor coactivators is essential for modulating steroid receptor-mediated transcription. This review will discuss the significance of nuclear receptor coactivators in modulating steroid-dependent gene expression in the central and peripheral nervous systems and the regulation of behavior. # 2009 Elsevier Ltd. All rights reserved.




Coactivators enable glucocorticoid receptor recruitment to fine-tune estrogen receptor transcriptional responses

Nuclear receptors (NRs) are central regulators of pathophysiological processes; however, how their responses intertwine is still not fully understood. The aim of this study was to determine whether and how steroid NRs can influence each other’s activity under co-agonist treatment. We used a unique system consisting of a multicopy integration of an estrogen receptor responsive unit that allows direct visualization and quantification of estrogen receptor alpha (ER) DNA binding, co-regulator recruitment and transcriptional readout. We find that ER loading is required for other type I nuclear receptors to be co-recruited after dual agonist treatment. We focused on ER glucocorticoid receptor interplay and demonstrated that it requires steroid receptor coactivators (SRC-2, SRC-3) and the mediator component MED14. We then validated this cooperative interplay on endogenous target genes in breast cancer cells. Taken together, this work highlights another layer of mechanistic complexity through which NRs cross-talk with each other on chromatin under multiple hormonal stimuli. 

https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/nar/41/7/10.1093_nar_gkt100/3/gkt100.pdf?Expires=1495847188&Signature=fDIJIa1Vn0wU~gJW-x~W99cNU35EmpNZZe80PhWGsajJ6V~IEh1Q64jnOBfjSel2I4GBWU1xijJIMJkaMLEq4evyklTgC5fm3bipGL6zWhj6SytBtPdAGhwp-svo5OikTAhIqYkDjIWJcT2pVH9LPMwtz5Ew5DyJ9sJSGA2NLaBwxDoqRJufZOnBvBFQbnuOnXPFt2dnAhw~h3jf-NI6s~RkfWeyhMoLpg2Th4F0gKpcWNGK1iJuegTQAZj5UvW51Po8-EXULUxMOrukUMjShkP2jPSkjRQujW-jlkWtnpVUvb7uvICZigUwD04YDqPNpZ1xp-7T6tZ260jCoGqKCw__&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q

Chromatin regulation

Histones undergo posttranslational modifications that alter their interaction with DNA and nuclear proteins. The H3 and H4 histones have long tails protruding from the nucleosome, which can be covalently modified at several places. Modifications of the tail include methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, citrullination, and ADP-ribosylation. The core of the histones H2A and H2B can also be modified. Combinations of modifications are thought to constitute a code, the so-called "histone code".[27][28] Histone modifications act in diverse biological processes such as gene regulation, DNA repair, chromosome condensation (mitosis) and spermatogenesis (meiosis).[29]

https://en.m.wikipedia.org/wiki/Histone