[Fournier2008] presents evidence that coadministration of bio-identical estrogen and progesterone
does not increase the risk of invasive breast cancer, whereas administration of unopposed estrogen or non-bioidentical
progestins (e.g. Provera™ = medroxyprogesterone acetate = MPA) does significantly increase the risk of breast cancer, as previously reported
by the Women's Health Initiative (WHI) study [Beck2012].
Numerous other studies support the relative safety of bio-identical hormones given in
physiological doses, compared with patented non-bio-identical pharmaceutical "frankenhormones": [Holtorf2009], [Moskowitz2006],
In addition, multiple studies show that use of oral contraceptives (containing non-bio-identical hormones) are linked with higher
risk of breast cancer [Collaborative_Group1996]; in particular, the progestin Levonorgestrel appears to be especially problematic
This issue has also been discussed in the popular press: [Somers2006], [Somers2009], [Somers2012],
Based on a study of three castrated patients with advanced carcinoma of the prostate gland,
[Huggins1941] made the sweeping generalization that "giving testosterone to a man
with prostate cancer is like adding oil to a fire." Subsequent studies of rats by [Noble1977] and humans
[Fowler1981] reinforced the notion that testosterone promotes prostate cancer.
Although Huggins was awarded a Nobel Prize for his work, and his theory has long been taught in medical schools, it has recently
been shown to be almost diametrically false. In particular, Huggins' model fails to account for the role of estrogen, dihydrotestosterone (DHT),
or hormone receptors in the promotion of prostate cancer.
More recently, [Morgentaler2008] has pointed out that prostate cancer is more prevalent
in men with low testosterone, and that in most cases, supplementing with testosterone is actually safe and beneficial [Morgentaler2011],
[Szmulewitz2009], [Morris2009], [Isaacs2012].
As will be discussed below, testosterone itself is protective; however, its metabolites
estradiol (E2) and dihydrotestosterone (DHT) are the hormones actually responsible for initiating breast and prostate cancer.
[Friedman2013] makes the case (see below) that without both E2 and DHT, initiation of breast or prostate cancer is not possible,
and that lowering local E2 and DHT levels reduces the risk of these cancers.
It is important to distinguish between systemic levels of E2 and testosterone arising from bio-identical hormone replacement therapy
(and measured in blood, urine, or saliva), versus the cancer-forming
high local levels of E2 and DHT arising from excessive conversion of testosterone to E2 or DHT inside the breast or prostate tissue.
[Friedman2013] further points out that in addition to high local levels of E2 and DHT, these hormones must interact with hormone receptors
in the breast and prostate named Estrogen-Receptor-Alpha (ER-A) and Membrane-bound Androgen Receptor (mAR), respectively, in order
to induce cancer, as described further below.
Apoptosis (also known as "programmed cell death") is a process that protects the body from defective or old cells, and is triggered
by the immune system when a cell appears to be problematic.
Cellular apoptosis is modulated by the balance between competing pairs of hormone receptors, which
control expression of the tumorgenic protein bcl-2 versus the anti-tumor protein p53, as discussed below [Friedman2007].
Bcl-2 is a key protein involved in the control of apoptosis, which is in turn regulated by opposing pairs of cellular hormone receptors [Kandouz1996]:
- Estrogen-receptor-alpha (ER-A) vs estrogen-receptor-beta (ER-B)
- Progesterone-receptor-alpha (PR-A) vs progesterone-receptor-beta (PR-B)
- Membrane androgen receptor (mAR) vs intracellular androgen receptor (iAR)
In each of these pairs of hormone receptors, the first receptor increases expression
of the tumorgenic protein bcl-2, which acts to protect the cell against normal apoptosis, thus promoting cancer.
In addition, mAR decreases the production of the protective protein AS3, while iAR increases the production of the protective protein AS3
[Friedman2013, pg 60].
It is useful to compare the relative affinities of the three main types of estrogen found in humans: estrone (E1), estradiol (E2),
and estriol (E3) [Friedman2013]:
Relative binding strengths of estrogen receptors for different estrogens
|Receptor ||Estrone ||Estradiol ||Estriol
|ER-A ||0.1 ||1.0 ||0.11
|ER-B ||0.02 ||1.0 ||0.35
As we see above [Zhu2006], [Friedman2007]:
- E1 has an affinity for ER-A that is 5 times greater than for ER-B, and thus promotes tumor development.
- E2 has an equal affinity for ER-A and ER-B, and promotes tumor development when ER-A predominates.
- E3 has an affinity for ER-B that is 3.5 times greater than for ER-A, and therefore is protective.
- However, E3 binds to ER-B only 35% as strongly as E2 does, so maximum protection provided by E3 requires that
E2 levels be low.
ER-B is also beneficial by reducing inflammation that is often seen accompanying both benign prostate hypertrophy (BPH) and prostate cancer
which suggests that inflammation is not a cause of prostate cancer, but rather an effect (marker) of low ER-B activity [ORWJr].
It is not clear [to Dr. Weyrich] whether ER-A itself promotes production of the anti-apoptotic protein bcl-2, or whether either
the homodimer formed by two ER-A receptors, or the heterodimer formed by one ER-A combining with one ER-B is the culprit.
In any case, high levels of ER-A promote formation of both the homodimer and the heterodimer, and high levels of estradiol promote
simultaneous activation of both receptor regions in either the homodimer or the heterodimer [Friedman2013, pg 48].
[Ricke2008] has shown that ER-A [ORWJr: or its homodimer or heterodimer] is necessary for the formation of prostate cancer,
which Dr. Weyrich considers to draw attention to ER-A, with the discussion of its homodimers and heterodimers being an interesting detail.
[Lofgren2006] has shown that in normal breast tissue, the activity of ER-A and ER-B are equal, and on balance does not promote
However, once cancer has been initiated, natural selection tends to increase the density of ER-A relative to ER-B,
since the more ER-A and the less ER-B a cell has, the more bc-2 is produced, and the greater protection the cell has against apoptosis
[Friedman2013, pg 51].
There is also a third kind of estrogen receptor, which is bound to the cell membrane (mER). Like ER-A,
it promotes production of the anti-apoptotic protein bcl-2 (at least in the case of breast cancer [Friedman2007];
it has not been studied in relation to prostate cancer, but Dr. Weyrich expects a similar action in the case of prostate cancer.
Based on the above, [Friedman2013] presents compelling evidence regarding the cause of prostate and breast cancer,
and a clear model, The Hormone Receptor Model, for both preventing and treating both these cancers, which are primarily driven by
hormonal imbalances, especially excess local tissue (not systemic serum) levels of estradiol on pro-carcinogenic estrogen-receptor-alpha (ER-A)
[Bonkhoff2008]. [Friedman2013, pg 81] lists five factors are necessary to initiate prostate cancer:
testosterone, dihydrotestosterone, estradiol, intracellular androgen receptor, and estrogen receptor-alpha.
Dr. Weyrich notes, however, that evidence presented by Friedman exonerates testosterone as a direct causative agent -
if the conversion of testosterone to dihydrotestosterone and estradiol is blocked (e.g. by 5-alpha reductase and aromatase inhibitors, respectively)
then testosterone is NOT sufficient to initiate prostate cancer - see below.
Note that the enzyme aromatase converts testosterone into estradiol, and 5-alpha reductase converts testosterone to DHT,
so inappropriate testosterone supplementation
can indirectly promote both prostate and breast cancer (by increasing telomere length and thus preventing apoptosis of tumorgenic cells),
if aromatase activity is not controlled [Friedman2007].
Support for this theory comes from a study in mice that shows that in the absence of ER-A, testosterone cannot induce cancer
PR-B is beneficial, since it up-regulates
which stops cancer growth [Lee2002] by at least three different mechanisms: promoting apoptosis of defective cells, assisting in DNA repair,
and inhibiting angiogenesis [Friedman2013, pg 88].
There are also two membrane progesterone receptors: mPR-5alpha and mPR-4. mPR-5alpha binds to 5alpha-pregnanes ("bad progesterone")
that is formed by the action of 5alpha-reductase, and promotes cancer growth.
mPR-4 binds 4-pregnenes ("good progesterone") and inhibits cancer growth in breast tissue [Wiebe2000].
These receptors have not been studied in relation to prostate cancer, but Dr. Weyrich expects a similar action in the case of prostate cancer.
The BRCA-1 and BRCA-2 genetic mutations disable the protective function of the PR-B, leaving the tumorgenic PR-A unopposed reign.
In persons possessing the BRCA-1 or BRCA-2 genetic mutations, progesterone supplementation is likely to promote prostate and/or breast cancer
Cellular apoptosis is also modulated by the balance between intracellular androgen receptor (iAR) and membrane androgen receptor (mAR).
iAR down-regulates production of the tumorgenic bcl-2, but mAR up-regulates production of bcl-2.
The enzyme 5-alpha reductase type II (5AR2) converts testosterone to dihyrotestosterone (DHT).
DHT has been shown to bind 5 times more strongly to mAR than testosterone, thereby having the net effect of being tumorgenic, whereas
testosterone favors the protective iAR.
Note however, that the androgen receptors have multiple functions, some of which are protective and some tumorgenic
[Friedman2007, pg 55].
The synthetic progestin Provera™ blocks iAR and thereby disrupts the protective effect of testosterone binding at that site [Birrell2007];
Other researchers have also noted that Provera™ disrupts estrogen receptors as well. Dr. Weyrich notes that, based on Le Chatlier's Law of Mass Action,
supplementing with extra testosterone when Proverea is administered can competitively overcome the blockage at iAR by Provera™.
Vitamin D also has an important role in modulating apoptosis.
The active form of vitamin D is 1,25-dihydroxyvitamin D3 (calcitriol), which is formed in the kidneys.
Calcitriol binds to the vitamin D receptor (VDR) and increases cell death in both breast cancer [Narvaez2001]
and prostate cancer [Guzey2002].
Low Vitamin D status therefore is expected to increase the risk of both breast and prostate cancer.