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estrogen receptors are not created equally.  ER-alpha is the predominant pro-stimulatory signal receptor, whereas the ER-beta is the inhibitory receptor signaling pathway.  SERMS are not created equally as well dependent on how they bind the respective ER receptors.

Thank you for sharing

Estrogen receptors alpha and beta show dominance in the proliferative phases, with alpha isoform predominating.  In the secretory phase, less expression of ER was present. ER alpha was predominantly expressed in the epithelial and stromal cells in the proliferative phase.  ER beta was predominantly expressed in glandular cells in the same proliferative phase.   in the luteal phase, ER alpha expression declined in the funtionalis layers.  ER alpha in the basalis remained unchanged.  ER beta in the functionalis layers also declined in the luteal phase.   No relative change was found in the weak expression of ER alpha/beta in the myometrium.

Estrogen receptors are one mechanism of the transmission of the estrogen signal.  The signal can be from estrogens themselves, estrogenic like compounds (xenoestrogens) and via non-estrogens like 3-beta androstane idol that interacts with ER beta to decrease prostate cancer cell proliferation.

estrogen related receptors play a role in estrogen signaling, though they don't bind estradiol. They bind estrogen related elements. Exact role is unknown. They are called "orphan" members of the nuclear family of receptors.

Great article!!  Nice discussion of the complexity of hormones.  Women on aromatase inhibitors can make estrogen from Testosterone.  This is important with estrogen sensitive cancer as in breast cancer.  This will occur via alternative pathways: Testosterone to DHT via 5 alpha reductase and then DHT to 3 beta androstanediol via 3 beta HSD.  3 beta androstanediol is a male hormone metabolite that binds to estrogen receptors.  The affinity is less than Estradiol, but appears to have a higher affinity for ER beta over ER alpha. 

ER-beta found throughout both the proliferative and secretory phases of the menstrual cycle.  ER-beta expression was higher in the proliferative versus the secretory phases, though not statistically significant.  This makes since as estrogen stimulation dominates the proliferative phase.  Additionally, ER-beta expression was found throughout all levels of the endometrium and the myometrium.

estrogen-related receptors.  There are 3 types: alpha, beta, and gamma.  These don't respond to estrogens, but to estrogen related elements

ER-beta expression appears to regulate estrogenic activity through ER-alpha expression.  Co-expression of ER-alpha and ER-beta is associated with reduced estrogenic signaling, indicating a significant counter regulatory role for ER-beta.

Very nice study.  The authors looked at normal prostate, early disease and late stage prostate cancer.  The authors found that ER beta expression, as a general rule, was lost as progression occurred to the high-grade dysplasias and grad 4/5 carcinomas of the prostate.  Early low/moderate dysplasia was associated with an increase in ER beta--the authors propose that this was due to an attempt of the basal epithelium to counter the paracrine effect of ER alpha.   In contrast, androgen receptors appeared to be equally expressed across all.

ER-beta inhibits ER-alpha activation of cell proliferation via cyclin D1 gene expression.  This points to ER-beta as a counter regulatory receptor to ER-alpha.  This explains how a loss of ER-beta expression is found to be associated with increased cancers.  

estrogen receptor Beta and alpha discussed in the endometrium through menstrual cycle.  This study focus' on human endometrium

another awesome article dealing with hormone metabolites. Physicians that don't understand metabolites and receptors may be doing more harm than good.   One of the mainstays of the treatment of metastatic prostate disease is androgen deprivation therapy.  This article requires a reassessment of this due to the DHT metabolite 3-beta androstanediol.  This metabolite is produced from DHT production via the enzyme 3beta HSD.  This metabolite binds to ER beta, an estrogen receptor, and inhibits proliferation, migration, promotes adhesion (limits spreading), and stimulates apoptosis.  This is contrast to 3-alpha androstanediol.  Androgen deprivation therapy will decrease 3-beta androstanediol.  This is the likely reason for the increased aggressive prostate cancer found in those men using 5 alpha reductase inhibitors.

Estrogen receptors and disease

ER beta appears to be expressed through the menstruation cycle with predominance follicular and early secretory phases. Contrast with ER alpha predominance in late follicular and early secretory phases.

ER beta and prostate cancer.  More aggressive prostate cancer is found to be associated with lower ER beta expression in the prostate.  this makes sense, as other studies have shown that ER beta in the prostate can induce apoptosis (cell death), which is a powerful mechanism to regulate uncontrolled growth as found in cancer.

environmental toxin, bisphenol A, shown to increase estrogen receptor and androgen receptor expression in the prostate.  Also, a shift from ER beta to ER alpha occurs, increase the inflammatory and proliferative signal.

good discussion of estrogen receptors and their role of estrogen signaling transmission.This article goes deep into coregulators, corepressors, cofactors, agonists, antagonists...

xenoestrogen exposure has been shown to increase ER alpha and ER beta in the pituitary.

5-beta androstanediol doesn't have affinity for androgen receptors, but for estrogen receptors. Affinity for ER beta exceeds that for ER alpha.

Estrogen Receptor Beta shown to inhibit growth and spread of breast cancer cells.  So, ER-beta should be evaluated to not only prevent/slow the growth of breast cancer, but to prevent the spread of breast cancer.  This study proposes that the loss of ER-beta is a seminal event in the development of breast cancer.