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Progesterone metabolites are present on the membrane of ER/PR + as well as ER/PR - breast cancer cell lines.  The balance of 5 alpha pregnane:3 alpha pregnane regulates tumor genesis.  Estradiol increased 5 alpha pregnane receptors as well as 5 alpha pregnane unregulated itself via autocrine activity.  The 3 alpha pregnenes, 3 alpha hydroxyprogesterone and 20 alpha-dihydroprogesterone, decrease the 5 alpha pregnane receptors via paracrine activity.

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.

New understanding in progesterone metabolites.  These are not waste products, but are indeed active. This in vitro study found the balance of 5 alpha pregnenes and 3 alpha pregnenes, particularly 3 alpha HP promotes carcinogenesis or inhibits.  These receptors were found in all 4 breast cell lines evaluated.  

Studies in breast cancer and prostate cancer have revealed different effects by ER alpha vs ER beta.  It is no surprise that the same effects are found in ovarian cancer.  This study found ER alpha antagonists and ER beta agonists "significantly" suppressed growth in the ovarian cancer cell lines SKOV3 and OV2008.  Also, ER alpha agonist and ER beta antagonist "significantly" increased growth in the same cell lines.  These findings point to in increased proliferation with ER alpha and decreased with ER beta.  This is consistent with breast and prostate cancer also.

Indole-3-carbinol degrades ER alpha expression on breast cancer cells lines and down regulates ER alpha expression.  Not only does I3C degrade ER alpha expression it inhibits its expression as well.    Additionally, I3C interferes with signaling associated with ER alpha through IGF-1.

The receptors for 5 alpha progesterone and 3 alpha hydroxyprogesterone are distinct from other hormone receptors.  These receptors are plasma membrane bound.  Through these receptors, these progesterone metabolites initiate autocrine and paracrine activity.  E2 increased 5 alpha progesterone receptors.  This is very important in ER-/PR- breast cancer, but does still have significance in ER+/PR+ cancer as well.

Progesterone metabolites play key role in breast cancer carcinogenesis or inhibition of carcinogenesis.  The key active progesterone metabolites discussed in this article are 5 alpha pregnene and 3 alpha hydroxyprogesterone.

Another support point for Estrogen as a cause of low Testosterone.  This animal study points to signaling of Estradiol through ER alpha.  This study found high expression of ER alpha and subsequent signaling by E2 decreased cAMP and Nur77 transcription factor.  Nur77 increases steroid synthesis.  This was confirmed with ER alpha knockout mice.

alpha lipoic acid inhibits NF-kappa B activation by inhibiting TNF-alpha

alpha lipoic acid found to improve insulin sensitivity and reduce oxidative stress and inflammatory markers.  In this study, IV ALA was given daily for 2 weeks, and the result was reduced oxidized LDL and all other lipids, improved insulin sensitivity, reduced TNF-alpha, IL-6, and 8-iso-prostaglandin, and increased adiponectin.

alpha lipoic acid improves glucose control in individuals with type II DM.  This study showed decreased lactic acid and pyruvate levels with alpha lipoic acid therapy.  Therapy in this study consisted of ALA of 600 mg twice daily.

alpha lipoic acid shown to reduce diabetic neuropathy in this review of 15 clinical trials.  The trials included both IV and oral administration of alpha lipoic acid.  Both routes of administration revealed positive reduction of neuropathic symptoms.

ER alpha and ER beta have different effects on the uterus in this mice model.  ER beta modulates ER alpha.  ER beta decreases PR, whereas ER alpha increases PR.

ER alpha increases aromatase expression in the prostate.  PGE2 increased the ER alpha receptor.  Vicious cycle in men.  Increased aromatase activity increases estrogen production which increases ER alpha (pro growth) and further aromatase activity.

Cause and effect cannot be taken from this study.  However, TNF-alpha is known to disrupt testicular function, in this case the study found decreased sperm motility, lower Testosterone levels, and increased LH and FSH at baseline.  Improvement was seen after anti-TNF-alpha therapy. The point of this study should be why the elevated TNF-alpha and attack there.

Study points to obesity and low Testosterone contribution of neuroinflammation.  No effect of body weight was seen with TRT.  This animal model found similar positive effects of TRT in insulin sensitivity.  Obesity and low T increase inflammatory cytokine production: this study found an increase in TNF-alpha and IL-1beta and TRT reduced TNF-alpha and IL-1beta to near base-line.  Testosterone is neuroprotective and this study reviewed the small volume of evaded that pointed to benefit from estradiol.  Testosterone's effect on glial survival was positive but not significant.  Obesity and low T were found to be associated with increased macrophage infiltration in the PNS with increased TNF-alpha and IL-1beta.   Testosterone therapy improved peripheral neuropathy via its positive effects on nocicieption.

T3 stimulation of TR-alpha increases ER-alpha transcription and COX-2

ER alpha promotes lung inflammation.  In this study, they found that ER alpha could be a potential target to reduce lung inflammation.

This study proposes that testosterone therapy aids in renal dysfunction in men.  However, they document that IL-6 and TNF-alpha and oxidative stress are a part of this process. What they fail to mention is that aromatase activity and conversion of T to E in men increases IL-6 and TNF-alpha.  Studies have also shown that T decreases TNF-alpha. Very likely, it is high aromatase activity causing the effects documented by this study.

Bisphenol A causes shift in ER-beta to ER-alpha through increase ER alpha transcription in the testis.  This only looked at ER expression in the testis.