in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative
about 90% of normal proliferating breast epithelial cells are receptor negative
Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure (Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
serum from mice with tumors had significantly more 5αP than 3αHP
the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and >10-fold higher 5αP than 3αHP levels
Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
breast carcinomas are able to synthesize progesterone
The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
5α-reductase and 5αPR levels are upregulated by 5αP
in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
Cesarean delivery and lack of breast feeding significantly alter gut flora. This has potential significant metabolic consequences--diabetes, asthma, obesity...The urge to deliver at convenient times may lay the foundation for our metabolic crisis in the US.
Glyphosate inhibits CYP 450 enzymes. The author states it well: "glyphosate enhances the damaging effects fo other food borne chemical residues and environnmental toxins. Additionally, Glyphosate disrupts gut bacterial function in the human gut. This dysbiosis is well known to cause systemic disease, such as obesity, diabetes...
Great confusion exists in the medical profession about Testosterone and PSA and the health of the prostate. The conversion of Estrogen, whether E2 or E1, and other variables are responsible for increases in PSA while on Testosterone therapy. This study points out that Estradiol in men stimulates cell line growth of prostate cancer. In contrast, Epitestosterone, an androgen metabolite, has antiandrogen, inhibits this estrogen activity. Epitestosterone exists in an inverse relationship to Estradiol and IGF-1.
Interesting animal study found that diabetic animals associated with increased aromatase expression in adrenal cortex, kidneys, and other tissue, androgen receptors were decreased in adrenal glands, and ER-alpha expression in the kidneys was increased by 159%.
The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain.
Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual
care did not reduce ovarian cancer mortality
post-menopausal (but not premenopausal) women at baseline who went on to develop breast cancer showed about a 15% lower 2:16alpha-OHE1 ratio than matched control subjects
Summary of 2010 report on marathons and the heart. Less fit runners can do significant damage to the heart i.e. fibrosis compared to fit runners. V02 max is a good way to assess aerobic endurance and differentiate between the two. Dr Larose showed via MRI that it can take 3 months for the heart to recover.
obesity has also been linked to preferential estrogen metabolism via the 16-alpha-hydroxylation pathway; thus,
a prediction of the mechanism by which obesity could increase breast cancer risk would be through a lowering of the 2:16 ratio
in favor of the 16 pathway
increased
BMI was associated with a lower 2:16 OHE ratio
Our data show a significant association between alcohol use, defined as at least one drink per day or an average of seven
per week, and 2:16 OHE ratio
An alcohol-induced rise in estrogens as a consequence of alcohol catabolism in the liver has
been reported
The only study that looked at the association between
alcohol and wine consumption in healthy women did not report a clear association
smoking has been reported to increase induction of the 2-hydroxylation metabolic
pathway (24). However, the few epidemiological studies conducted on healthy women showed no difference in estrogen metabolites with smoking
status (22) or smoking dose (20), in line with our findings.
Family history of a first-degree family member with breast cancer confers a 2- to 4-fold risk of developing breast cancer
16% of breast cancers are due to unidentified hereditary
factors
Estrogen metabolism occurs through enzymes whose activity is determined
by the presence of specific genetic polymorphisms, thus can be defined as unique to each individual.
the metabolism
is also influenced by a number of environmental factors, which change over a lifetime
significantly lower 2:16 OHE ratio in women who have known breast cancer risk factors
compared with healthy women
There was an additional significant association specifically with BMI and alcohol use, which
also supports the evidence that these factors affect estrogen metabolism
Profiling estrogen metabolites may identify women
who are more likely to develop breast cancer within a population of women with known risk factors
urinary estrogen metabolites shown to provide insight into breast cancer risk. This study suggested that a low 2:16 OHE ratio increase breast cancer risk.