SECTION 6—2-Sex
and related hormones, fine
tunes autophagy 9/13/202019

Chapter
2, Sex hormones and others hormones fine tune autophagy: 1. Sex hormone connection 2. InCHIANTI longevity study 3.
Sex hormones benefits 4.
Estradiol and testosterone protect MTD
5. Testosterone, and neurosteroid
6. Estradiol HRT is healthful
7. HERS, WHI, horse estrogen and MPA
8. Osteoporosis and estrogen 9.
Epidemic of osteoporosis and osteoarthritis
10. My historical note on hormones
11. Why menopause and andropause?
12. DHEA and DHEAS introduction
13. DHEA turns on autophagy 14.
DHEA neurosteroid 15. IGF-1 and
InCHIANTI Study 16. IGF-1 autophagy,
and CC for MTDD 17. Pregnenolone a
major neurosteroid 18. Progesterone and
progesterin 19. Neurosteroid summary 20.
Testosterone, estradiol 21. An
historical note on hormones
Steroid hormonal connections to CAWD: a
good story their history; it illustrates another sad chapter in the history of
“modern medicine”. Again, I must thank
Marcia Angell for her eye-opening book on how pharma functions (see appendix). I
was still under the delusion of Keynsian
economics with managed capitalism in the area of health care. To put it
another way if pharma can set up
as standard care lowering cholesterol and avoiding saturated fats, and gain
government support for the lipid hypothesis, then they can change the way we do
medicine for to maximize profits. So,
what is the evidence for steroid and where is the carpolla? There are receptors in every cell for
them including
the mitochondria, and a number of tissues can manufacture them. Nature functions to survival to promote
survival and thus passing of the genes, but also to cully the burden of the elderly
from the village. Reducing sex steroids functions
in the mitochondria as to its functions through a reduction in their synthesis promotes
less ATP and thus a weakening of the immune system with its infectious consequence.
Sex hormones in the broader family are a vital part of an optimally
operating autophagy system. Of
particular interest are the sex steroid testosterone, dihydrotestosterone,
estradiol, DHEA, and progesterone and their structurally related steroids. Strong
evidence is for testosterone,
estradiol, “Both
steroids trigger a complex molecular mechanism that
involves crosstalk between the mitochondria, nucleus, and plasma membrane, and
the cytoskeleton plays a key role in these interactions. The result of this
signaling is mitochondrial protection.” [1] of these I have reviewed in depth the
literature on the sex hormones, pregnenolone,[2]
DHEA, and progesterone along with the growth factor IGF-1 and IGF-2. The chart
of above gives you some idea of the number of sex hormones, and thus the
Herculean task of sorting out their functions and interactions. Steroid
hormones are cholesterol derivatives that serve as
signaling molecules to coordinate the expression of complex gene programs in
higher eukaryotes. These molecules exert their effects by diffusing into cells
and interacting with specific intracellular receptors. Receptors for each of
the major classes of sex and adrenal steroids have been characterized. In the
absence of their cognate ligands, the steroid hormone receptors remain
sequestered in the cytoplasm through interactions with large multiprotein
complexes containing heat shock proteins. However, the binding of ligand causes
the steroid hormone receptors to be released from these complexes and
translocated into the nucleus. Once inside the nucleus, the activated receptors
regulate the expression of target genes by binding as homodimers to short DNA
sequence motifs, termed hormone response elements (HREs). In this manner, the
steroid hormone receptors function as ligand-activated transcription factors. .
. . In addition to receptors with
established ligands, approximately 30 other members of the nuclear hormone
receptor family have been isolated from vertebrates. [3] They are synthesized in
the gonads, adrenal cortex, and some other tissues including in the brain by the
glial cells.[4] Because pharma frames the topic, their
function as neurosteroids has been buried.[5]
“Neurosteroids
affect synaptic functioning, are neuroprotective,
and enhance myelinization.
Pregnenolone and its sulfate ester may improve cognitive and memory
function. In addition, they may have protective effects against schizophrenia.”
[6] There are many other health
benefits independent of autophagy, such as
neurosteroids, androgen effects, lipo regulators, mitochondrial functions, etc.
There is much to gain from understanding their importance of these steroids. Given
the many functions of the steroids made
from cholesterol, the war on cholesterol and these steroids is another example
of pharma profiting from illness. I
shall let the evidence do the talking.
Nature doesn’t evolve such a large number of steroids to harm
mammals.
Yes, again we have a case of pharma promoting
illness and again I am responding to the harm done. Again we have pharma tell
us that something
which is healthful causes illness and framing the topic for their ends. Again
we have pharma “proving” that nature’s
systems making us sick, in this case with the sex hormones.[7] And again there is a mountain of journal
articles proving the opposite. This
chapter both exposes their crapolla and
also supports theme in this Section of the healthful fixes. Natural hormones
are very healthful; and low
levels are associated with age related conditions and morbidity both in LSPs
and HSPs. They are more than merely a
marker, because natural hormones play key homeostasis functions and autophagy.
For
simplicity, I will avoid the complexity of 17 related sex hormones (diagram
above) and their many functions since the science is weak and a discussion
contributes little to the focus of this book.
The research is thin because sex hormones are natural, they can’t be
patented, and they are healthful.[8] There is much more to the sex steroids then
the development of sexual characteristics.[9] These other functions are the reason that
nearly every cell has special receptors for them, estrogens, testosterone,
dihydrotestosterone, pregnenolone, and DHEA—and nature expends the ATP to
promote wellness. Pharma makes hormone
mimics for sake of patents and to promote illness. It is why Prempro in the
U.S. is most popular
HRT and the worse (#7).[10]
I am
focusing on estradiol, DHEA, and testosterone, since there is strong evidence
for their health benefits. The cancer
association is the work of bad pharma.[11] I had for 15 years settled for association of
the health benefits of these 3 hormones[12]
now I found the why. I went from prevention
happened in the black box, to a rough diagram of the workings of the black
box. If they are so good they should
extend life.
2. InCHIANTI Longevity study: Relying
on the InCHIANTI Study of men followed 6 years, the cohort with the lowest 1/4th
of all 3, testosterone, DHEAS, and IGF-1 (insulin like growth factor 1—there
are 2) had a death rate of 2.44 higher than the 3/4th above them.[13]
Several lines of evidence suggest that the aging
process is associated with a decline in anabolic hormones and increase in
catabolic hormones.22 In this
study, we evaluated the 3 key anabolic hormones: bioavailable testosterone,
DHEA-S, and IGF-1. Each of these
anabolic hormones has a direct impact on lipid and glucose metabolism.23-25 evidence has indicated that low testosterone,
IGF-1, and DHEA-S levels are good predictors of cardiovascular disease and
diabetes in men.5,10,26
Furthermore, we have previously shown that a low testosterone level is
inversely related with inflammatory markers and predicts the development of
anemia in the older population.27,28 Both
cardiovascular disease and anemia are 2 independent predictors of mortality in
older men.29 … Compared with men with levels of all
hormones above the lowest quartile, men with 1, 2, or 3 hormones in the lowest
quartile had an HR for mortality of 1.47 (95% CI, 0.88-2.44), 1.85 (95% CI,
1.04-3.30), and 2.29 (95% CI,
1.12-4.68) (test for trend, P = .006), respectively (Table 2). After
adjusting for confounders, including age, BMI, educational level, smoking,
alcohol and caloric intake, physical activity, log (IL-6) levels, and chronic
disease such as diabetes, hypertension, peripheral artery diseases, coronary
heart disease, congestive heart failure, stroke, Parkinson disease, COPD,
asthma, and cancer, the HRs for mortality were 1.04 (95% CI, 0.56-1.95), 1.34
(95% CI, 0.67-2.65), and 2.44 (95%
CI, 1.09-5.46), respectively (test for trend, P <.001) (Table 3). [to have all 3 in the lowest 25% entail after
adjusting for existing confounding variable a 2.44 death risk above the first 3
groups. In other words, the healthies of
the low hormones still died at a much higher rate than the healthiest of the
75% group]. . . . The mortality rates
(events per 100 person-years) were 2.9
in
group 0, 6.2 in group 1,
16.7 in
group 2,
and 46.0 in group 3 (P = .007,
test for trend).[14]
This raises
the
question as to how the 2 sex hormones and IGF-1 can be associated with health,
and thus life extension. The connection
of testosterone[15] and estradiol with autophagy comes in many
directions, and there are other healthful effects for the sex hormones. Given
the difference of only one functional
group and a ring structure, explains why both through autophagy have the same
benefits.[16] [17] DHEA and IGF-1 will be discussed at the end
of this subsection. Note: based
on my extensive review of the
literature I am assuming that estradiol, if women were included in InCHIANTI
study, would have resulted in similar positive result. Including estradiol. So what are the benefits and why?
[1] Vasconsuelo,
Andrea, Lorena Milanesi, et al, Sept 2013, Actions of
17β-estradiol and testosterone in the mitochondria and their implications in
aging
[2]
“Pregnenolone and its 3β-sulfate, pregnenolone
sulfate, like DHEA, DHEA
sulfate, and progesterone,
belong to the group of neurosteroids that are
found in high concentrations
in certain areas of the brain, and are synthesized there.” Wiki
pregnenolone June 2019.
[3] Kliewer, Steven, John Moore, et al, Jan 1998, An Orphan Nuclear
Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway
[4] Wiki, Glia, Sept 2019. Glia, also called glial cells
or neuroglia, are non-neuronal cells in the central
nervous system (brain and spinal
cord) and the peripheral
nervous system. They
maintain homeostasis, form myelin, and
provide support and protection for neurons.[1] In the
central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal
cells, and microglia, and in the peripheral
nervous system glial
cells include Schwann
cells and satellite
cells. They have
four main functions: (1) to surround neurons and hold them in place; (2) to supply
nutrients and oxygen to
neurons; (3) to insulate one neuron from another; (4) to destroy pathogens and remove
dead neurons. They also play a role in neurotransmission and synaptic
connections,[2] and in
physiological processes like breathing.[3][4][5] While glia
were thought to outnumber neurons by a ratio of 10:1, a recent study provides
evidence for a ratio of less than 1:1.[6] . . . Glial cells make up about half the
total volume of the brain and spinal cord. The glia to neuron-ratio in the cerebral cortex is 3.72 (60.84 billion
glia (72%); 16.34 billion neurons), Wiki, Glial, June 2019.
[5] Fifteen
years (2019) after reading hundreds of journal articles—mainly in search of
their benefits—did I come across their production in the brain and function as
neurosteroids. If mentioned, it wasn’t
stressed. I have long before 2004
considered the modus operandi essential, what separates a pill pusher from
medical scientist.
[6] Wiki, neurosteroids, Sept 2019
[7] By
showing the evidence is contrary what the NIH and KOLs spout, I am again
confirming the dismal assessments of Relman and Angell in the introduction
section. This confirms Goldacre
assessment: “They frame the topic.”
[8] A
patent can be obtained if mixed with a patented drug which is why a progestin
is added to estradiol. The FDA has given
out patent now on the lowest of standard, such as adding an over-the-counter
drug such as acetaminophen, a slow release formula, ancient drugs such as
colchicine, and now what our body makes such as allopregnanolone whose branded
name is Zulresso, and has for a course of treatment for postpartum depress a
cost in the US of $34,000. Wiki
allopregnanolone, April 2019.
[9]
Many of the sex steroids are neurosteroids and some act as positive allosteric
modulators of GABA receptors. The
functions upon the mitochondria in the brain entails superior mitochondria
functions, until andropause and menopause.
[10]
It is why hormone mimics such made by soy beans, and some of the progestins are
bad for health, they occupy those receptors and block some or all of the
positive effects of the natural sex hormones.
[11] I
had failed to find, after several hours of searching, an article clearly
showing an increased risk of uterine cancer for unopposed natural
estrogen. A similar sham has been worked
with testosterone and prostate cancer.
The Harvard Professor Abraham Morgentaler, has done the research and
published it both in a journal article, and in his book Testosterone for Life. See his chapter 7, pages 115 to 139. He found in research using the archives of
the Harvard University Medical Library, the 1941 article by Drs. Huggins &
Hodges that started the myth; their finding was based on a single patient who
had been castrated. The 1981 study done
at the Memorial Sloan-Kettering Cancer Center over the course of 18 years on 52
men with terminal prostate cancer, that all but for had been castrated or given
estrogen (the same hormonal effect). The
increase in cancer growth rate occurred with the re-introduction of
testosterone by injection. (the results
for the 4 not castrated were not given in the article.) Morgentaler calls the
increased growth a flare phenomenon. Millions
of men have been castrated for
profits, and I believe many more women, because not only with uterine cancer is
the ovaries removed but also with the hysterectomy. The myth of cancer growth
has a horrific
price. This happened to my 2nd mother-in-law, who was also put on
valium. The quality of her remaining 36
was poor. They included depressions,
mental institutions, electroshock treatment, drugs, and cancer 3-times over 20
some years.
[11]
As usual I must cherry pick the evidence based upon my understanding of how
cells function, pharma functions, and evolution.
[12]
The fourth would be progesterone; however, in my review of the journal articles
the evidence is supporting its healthful functions were less, and thus I
couldn’t include it in the list. Besides
the 3 contribute to an increased level of progesterone, if needed. I have not
after several hours been able to find out the role of progesterone in males.
[13] Maggio,
Marcello, Fulvio Lauretani, Et al, Nov 2007, Relationship between low levels of anabolic
hormones and 6-year
mortality in older men: the aging in the
Chianti Area (InCHIANTI) Study.
Again, we have the case of a hatchet job by pharma on the benefits of
DHEA. (The sulfate is the storage form
of DHEA.) The best way to take it to
avoid the liver catabolism of DHEA is sublingually. Supplements with the sulfate
group I haven’t
been able to find. The reason might be
as dark as that with low dose aspirin, enteric coated aspirin, taking a statin
in the day when the body makes cholesterol at night, and so on.
[14] Maggio,
Marcello, Fulvio Lauretani, Et al, Nov 2007, Relationship between low levels of anabolic
hormones and 6-year
mortality in older men: the aging in the
Chianti Area (InCHIANTI) Study
[15] Gao,
Fengyi, Guoping, Li, et al, April 2018, Autophagy regulates testosterone
synthesis by facilitating cholesterol uptake in Leydig cells¸ This article shows the role of autophagy upon testosterone
levels.
[16] While
some would consider the difference in CVD a counter example, this is another
case of association leading to the wrong conclusion. For LSP both sexes are
at extremely low
risk. As of now, I am not aware of the cause for
this difference in HSPs.
[17] Vasconsuelo,
Andrea, Lucia Pronsato, et al, Nov 2011, Role of 17β-estradiol and testosterone
in
apoptosis
|
3.
Sex hormone
benefits:
TESTOSTERONE
ESTRADIOL DEHYDROEPIANDROSTERONE
 
The evidence in support of restoring hormones to a youthful
level is solid;
the evidence for unnatural analogues is mixed (#6 is on pharma’s hatchet
job with the NIH using Prempro, horse estrogen
and medroxyprogesterone in the WHI study, the most-costly of their
studies). A large body of studies
support hormone replacement therapy (HRT,
estradiol and a progestin for women and for men testosterone). Because the sex hormones
are neurosteroids, promote autophagy, and partially regulate a number of bodily
functions there is a diverse long list of benefits, which are supported by
journal articles (see links thereto below on my website). Testosterone reduces mitochondrial dysfunction,
insulin resistance, fat mass,
depressed mood, inflammation, vascular aging; increases/improves muscle strength,
erythropoiesis, collagen in
skin, sexual interest and cognitive and brain functions in general including
mental health (it is a neurosteroids); reduces
risk for dementia, T2DM, osteoporosis and bone fractures, rheumatoid
arthritis, cardiovascular disease, atherosclerosis, reduces rate of morbidity
and there are more benefits. All these claims are supported by journal articles,
which are to be found for testosterone at http://healthfully.org/rc/id7.htm
and a similar list for estrogen and a
progestin:[1]
with evidence in addition for these reduces risk macular degeneration and
increased health through positive effect upon collagen in the skin and
breasts. With 38% of women having taken
HRT by the 1990s (no figures for men) pharma took notice and the NIH did two
large trials using the worst of the HRTs; the results had the desired effects
upon belief and usage of HRT among women.
For a review of the benefits
with links go to my published articles on HRT for men (http://healthfully.org/rc/id7.html)
and for women (http://healthfully.org/rc/id2.html)
article and my collection of journal article
for men (http://healthfully.org/malehormones/)
and for women (http://healthfully.org/fhr/).
Four
often missed facts: First, that
estradiol though not an androgen, it has a very significant androgen effect
through conversion into testosterone—about 10%.
Second is the muscle loss of aged women can be prevented with a
significant daily dose of estradiol, testosterone, or DHEA. Sarcopenia (frailty
from lack of muscle) has
a major impact upon health and quality of life. Third is that muscles are a
demand system, thus muscle gain from HRT requires significant resistant
training.[2] Without weight training, there won’t be an
increase in muscle mass, thus another way for pharma to “prove” that there
aren’t physical benefit for HRT. Fourth
point missed is that estradiol slows the loss of calcium in bone, and this
slows remodeling, while progesterone increases remodeling, thus the two operate
as a system for rejuvenation of the bones; thereby making bones less brittle (#7). As
a demand system, bone benefit from impact
training such as running and jumping rope, as too the cartilage. Runners have
less joint problems. Point 2, 3, and 4 also apply to men.
4. Testosterone
and estradiol protect the
mitochondria:
Consistent with MTDD causing CAWD, that
hormones that promote mitochondrial functions would lower risks for CAWD. The
evidence including the modus operandi has
been demonstrated for estradiol and testosterone: “Our
results indicate that testosterone improves cell survival and
mitochondrial membrane potential and reduces nuclear fragmentation and reactive
oxygen species (ROS) generation.”
[3]
Estradiol and testosterone enter the MTD and improve functions therein:
A decline in the mitochondrial
functions and aging are two
closely related processes. The presence of estrogen and androgen receptors and hormone-responsive
elements in the
mitochondria represents the starting point for the investigation of the
effects of 17β-estradiol and testosterone on the mitochondrial functions and
their relationships with aging. Both steroids trigger a complex molecular
mechanism that involves crosstalk between the mitochondria, nucleus, and plasma
membrane, and the cytoskeleton plays a key role in these interactions. The result
of this signaling is mitochondrial
protection. Therefore, the molecular components of the pathways activated by
the sexual steroids could represent targets for anti-aging therapies. In this
review, we discuss previous studies that describe the estrogen- and
testosterone-dependent actions on the mitochondrial processes implicated in
aging.[4]
I was surprised to find in the
strip-down mitochondria receptors for steroids; there value must be major benefits
to justify the production of these receptors.
Steroid
receptor-dependent interactions with mitochondria may include transcriptional
regulation of nuclear DNA-encoded mitochondrial proteins, transcriptional
regulation of mitochondrial DNA-encoded proteins, or indirect effects on
mitochondria due to interactions with cytoplasmic signaling peptides and
non-genomic control of cation fluxes. These interactions may play a role in
mitochondrial-dependent processes of oxidation. . .. STEROID
RECEPTORS IN THE MITOCHONDRIA: The
prevailing view of the nucleus as the site of steroid receptor action, while
mitochondrial action is regulated by secondary messengers, has been challenged
in the last decade. Several studies demonstrate the existence of steroid
receptors in mitochondria. . .. Similar evidence [to glucocorticoids] exists
for localization of estrogen receptor (ER) α and ERβ to the mitochondria. . ..
These relatively nonspecific results led to more conclusive evidence that the
estrogen binding was mediated by a true receptor using specific antibodies. .
.. In previous work from our laboratory,
we have cloned and expressed a novel PR [progesterone], termed PR-M, from human
adipose and aortic cDNA libraries.[57]. , . . STEROID
AND MITOCHONDRIAL INTERACTION; There are several mechanisms whereby steroid
hormones may affect mitochondrial function. These include transcriptional
control of mitochondrial proteins encoded by nDNA, transcriptional control of
nuclear-encoded transcription factors affecting nDNA-encoded mitochondrial
proteins, transcriptional control of mitochondrial proteins encoded by mtDNA,
activation of cytosolic signaling peptides by plasma membrane or cytosolic
steroid receptors that subsequently affect the mitochondria, and possible
non-genomic effects by a mitochondrial membrane-bound receptor. . .. Estrogen
may indirectly affect mitochondria
by activation of MAPK. . . . Non-genomic
actions of estradiol in the mitochondria have also been demonstrated. Estradiol
and other agonists caused an immediate increase in mitochondrial Ca2+ in HeLa cells via the
mitochondrial Ca2+ UP. [5]
That
which is good for the MTD, must also be good for the ATP hungry brain.
5. Testosterone and neurosteroids: As an anabolic steroid testosterone improves
the quality of life and functions of elderly men and women who will experience
significant muscle loss. Falls are by
the 7th decade a significant contributor to mortality. In addition,
like estradiol, the addition of
testosterone prevents additional bone loss through positive bone remodeling (#7), and also like DHEA and estradiol it is a
neurosteroid,[6]
and like them is also synthesized in the brain and other peripheral tissue
(more on this below). In the brain it
has psychological functions and reduces the risk for psychiatric conditions and
dementia. Testosterone is a steroid
(derived from cholesterol) in the androstanes class that binds to a
testosterone receptor. Testosterone
increases insulin sensitive and thereby reduces the risk for t2d and weight
gain, reduces inflammation and convulsive seizures,[7] reduces emotional issues,[8] improves cognitive
functions and sexual performance, increases erythropoiesis, reduces risk for
CVD and MeS, lowers risk of prostate cancer, and other positive effects.[9] The variety of benefits come testosterone’s
upregulation of autophagy.
In
the brain it functions not as a steroid, but through neurotransmitter receptors
or directly/indirectly as a modulator of neurotransmitters. Testosterone is
converted in the brain to
3-beta androstanediol which is a potent positive allosteric modulator of GABAA
receptors and an agonist of ERbeta.[10] [11] .
Testosterone functions both as a neurosteroid
and a precursor of other neurosteroids
and low testosterone and other neurosteroids are CC for neurodegenerative and
mental illness, 4:3.
“Neurosteroids, including
pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG) and
their derivatives [testosterone and estradiol] that are synthesized in the
presence of the steroidogenic enzymes [4, 18, 24, 28]. The first step in the
biosynthesis of neurosteroids is the conversion of cholesterol to
pregnenolone. Progesterone affects
neuronal growth, survival and differentiation,
causes regression of neuritic extensions before they have established contact
with other neurons or glia, and protects neurons from death induced by
picro-toxin [9]” [12] Neurosteroids are synthetized in
the central and peripheral nervous system, particularly but not exclusively in
myelinating glial cells, from cholesterol or steroidal precursors imported from
peripheral sources.[13]
A
table lists the neurosteroids and
their protective functions at page 337. Many of the steroid find functions in
the brain. Studies have been done on a
number of them because they promote healing following injury, for which
progesterone has been the most investigated.
“Progesterone (PROG) is also a neurosteroid, and
a progesterone
receptor (PROG-R) has been identified in peripheral and central glial cells.” [14] The article goes on
to include neurosteroid functions
The lists and types of benefits
for
testosterone is long:
Testosterone,
a gonadal hormone, modulates aggressive and
sexual behavior (Christiansen, 2001), has anxiolytic and
antidepressant-like effects (Carrier et al., 2015), affects cognition (Cherrier, 2005), and regulates synaptic
plasticity in the brain (Hatanaka et al., 2015). Moreover, testosterone
has been shown to prevent neuronal cell death, to improve memory after damage (Fanaei et al., 2014), and to regulate the
activation and reactivity of glial cells upon brain injury (Barreto et al., 2007). The neuroprotective
actions of testosterone may in part explain that
the decrease in its plasma levels with aging is associated with an increase in
neurodegenerative diseases (Bialek et al., 2004; Gold and Voskuhl, 2006; Rosario et al., 2011; Barron and Pike, 2012; Khasnavis et al., 2013). Furthermore, testosterone
may be converted into estradiol by aromatase, or dihydrotestosterone (DHT) via
5α-reductase, and part of the protective effects of testosterone might be due
to its metabolites (Barreto et al., 2007).[15]
For a longer
list of
benefits of testosterone with links go to http://healthfully.org/rc/id7.html; for mechanism of
protection #4.
Because of our western diet there are
pathogenic consequences; thus as a neurosteroid, testosterone turns up the heal
process for a long lists of signs of the damage caused by the western diet
through MTDD and RATP. Drugs in general
don’t repair the causes just modify the behavioral consequences. The situation
is like that of putting air
into a flat tire; a better fix is to repair the MTDD though autophagy. So again
I recommend dealing with the basic
cause and to undo MTDD.
Testosterone
functions in the autophagic processes entails that an abnormal reduction such
as through castration has significant functional and health consequences; abnormal
low levels pathogenic consequences.[16] [17] This observation raises an interesting
question/puzzle. There has been over the
last 100 years a very significant decline in the level of testosterone among
the elderly. Could this decline be
contributing to the divergence in life longevity of men from that of women
(averaging about 5 years in most countries on the western diet). Those with
the lowest level die sooner,[18] and is there such an association in the
LSPs? And does HRT for men reduce this
difference
in longevity? I have yet to find any
longevity studies on point. Secondly, I aver
that
this is secondary to MTDD, which could be more significant among men; again I haven’t
found
studies on point comparing MTDD degrees for the 2 sexes.


These
chart support my contention that with increasing MTTD many systems are down
regulated, and as the InCHIANTI Study (#3) which shows 3 hormonal
markers better
indicator of morbidity than just one.
This support my thesis that the effects of MTDD effect many system which
explains why 3hormones are a better marker than l for MTDD.
In 5:4 are supplements I would take under various
situations including testosterone, I do not here wish to drag out the topics
related to bad pharma but if you are interested again I refer you to my terse
paper on testosterone, which also goes over its benefits, all with links[19] Among them is my
observations on testosterone. For those
who wish to read more on the topic, the best in print that I have found is Testosterone for Life by Harvard Professor Abraham Morgentaler, His research
and published is published in journal articles, including the tobacco science
which is used to scare the public with a warning about prostate cancer. About
the benefits of testosterone, it is
similar to estradiol but as an androgen it is and androgen.
6. Estradiol HRT is healthful: Estradiol has been well-established as a
neuro-protector both for healing following an injury and the prevention of
neurodegenerative conditions. HRT has
been shown in men and women to improve cognitive functions. “Newer
studies showing rapid effects of estradiol on consolidation of memory through
mem brane interactions and activation of inter-cellular signaling pathways
are reviewed as well as studies focused on traditional genomic
mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and
possible actions as a neurosteroid
to promote memory are discussed. “ [20] [21] It has been shown to following a cerebral
ischemic event to inhibit apoptosis by increasing autophagic cellular repair.[22] “It is also protective of mammary epithelial
cells (MEC) by a tightly controlled balance be reparative autophagy and apoptosis.”
[23] The many benefits of estradiol is through the
upregulating of autophagy.
Electron microscopy revealed that in cells overexpressing
EIG121, autophagosomes were markedly increased. Overexpression of EIG121 also
increased the cells containing acidic vesicles and induced lysosomal
degradation of long-lived proteins. In MCF-7 cells, both EIG121 and LC3 were
rapidly degraded by a lysosomal mechanism after starvation.[24]
Our study reveals a unique mechanism through which ERβ/PTEN signaling
induces cell death in TCAM2 by autophagy and necroptosis[25]
The net result through autophagy
is a lower
cancer rate, which has been demonstrated with HRT (Europe where Prempro usage
was much lower). “Estradiol
(EST) reduces the risk of stroke and decreases the incidence and progression of
the disease because of its neuroprotective roles in inhibiting cell death that
occurs in response to a variety of neuronal stimuli such as inflammation and
oxidative stress.” [26]
The reason for the reduced apoptosis lies in its alternative, autophagy, which
is not easily observed. Autophagy
repairs the cells and thereby reduces the rate of apoptosis. This is just one
of more than 20 benefits I
have found from maintaining a youthful level of estradiol and much tobacco
science against the natural hormone—at http://healthfully.org/rc/id2.html--.
“Cancers in women who use HRT are often less advanced,
and lower
mortality has been reported in those who use HRT than in nonusers. . . . The association of HRT with lower
proliferation rate and smaller tumor size was exclusively caused by ER-positive
tumors.”[27] In a study using estradiol, the most active
of the 4-human estrogens and the progestin norethiserone in a tri-cyclic
formula (by Novo Nordisc), the results were for 501 women on HRT compared to
the control group of 502 confirm
Results: At
inclusion the women on average were aged 50
and had been postmenopausal for seven months. After 10 years of intervention,
16 women in the treatment group experienced the primary composite endpoint
compared with 33 in the control group (hazard ratio 0.48, 95% confidence
interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to
1.08; P=0.084). The reduction in cardiovascular events was not associated with
an increase in any cancer (36 in treated group v
39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in
treated group v 17 in
control group, 0.58, 0.27
to 1.27; P=0.17).[28]
These
positive results though better than other studies, follow the pattern that HRT
is good for health.
With the synthetic hormones (other than
Prempro, the leading US HRT) the benefits include lower risk of Alzheimer’s
disease and other types of dementia, cancers, cognitive decline, CVD, MI,
stroke, ischemic events, depression, diabetes, obesity, osteoporosis rheumatoid
arthritis, and on the upside are increased sexual satisfaction, mood elevation,
firmer breasts, healthier skin (less wrinkles), at http://healthfully.org/rc/id2.html. A journal article on
point is Ten
reasons to be happy about hormone replacement therapy: a guide for patients: [29]
During
the last 30 years, there has been an overwhelming number of observational studies
demonstrating that HRT protects against ischemic heart disease, osteoporosis,
deterioration in cognitive function, colorectal cancer, the reduced incidence
of macular degeneration, as well as providing a decided improvement in
quality-of-life, such as vasomotor symptoms, urogenital atrophy, insomnia, and
general wellbeing. . . . the risk of death was lower among the
HRT survivors; odds ratio 0.28 (95%
confidence interval 0.11–0.71). [30]
Considering
that this
matching studies with a death rate of just over one fourth of those who didn’t
receive HRT, those without metastatic breast as standard treatment should be
given HRT, irrespective of without estrogen receptors (ER).[31] These results and the reports of other
benefits follow the pattern of autophagy promoting health. And the results are
far, far better than
those for the quasi-estrogens such as tamoxifen. I can only wonder, given the
variety of HRTs
used, including the leading Prempro, how much better the results would be for
estradiol. Unfortunately, there are no quality
studies of
conjugated natural human female
hormones, estradiol and progesterone, and that includes for all cancer.[32]
So what is Pharma’s response to a drug that
prevents
illness? To give the flavor of
independence and serving the public, there were 2-government funded “landmark”
studies to evaluate HRT. Given the size
of the studies and the experts involved, the selection of Prempro, horse
estrogens with medroxyprogesterone, the worst of HRTs was deliberate. The HERS
(Heart and Estrogen/Progesterin
Replacement Study) and WHI (Women’s Health Initiative were used to overturn the
strong evidence supported practice of recommending HRT during menopause and
continuing it afterwards because of its many health benefits.
[1]
Estradiol like testosterone is when taken orally transported to the liver where
it is metabolized, thus estradiol bioactivity is 5% and testosterone even
lower. Progesterone is poorly absorbed,
thus and for reasons of patent of exclusivity the synthetic forms of estrogen
and progesterone (progestin) are marketed.
Synthetic versions of testosterone have a small percentage of the
market, and common form administered is that of a patch constructed in a way to
obtain a patent. The results should be
better for the natural hormone with progesterone with estradiol obtain from a
compounding pharmacy. There aren’t studies
done on them for financial reasons, they can’t be patented, and the main
market through physician has been closed by guidelines, misinformation, and not
being covered by insurance companies.
[2] Guo,
wen, Siu Wong, et al, Dec 2012 Testosterone Plus
Low-Intensity Physical Training in Late Life Improves Functional Performance,
Skeletal Muscle Mitochondrial Biogenesis, and Mitochondrial Quality Control in
Male Mice
[3] Toro-Urrego, Nicolas, Luis Garcia-Segura, et al, June 2016, Testosterone Protects Mitochondrial
Function and Regulates
Neuroglobin Expression in Astrocytic Cells Exposed to Glucose Deprivation
[4] Toro-Urrego, Nicolas, Luis Garcia-Segura, et al, June 2016, Testosterone Protects Mitochondrial
Function and Regulates
Neuroglobin Expression in Astrocytic Cells Exposed to Glucose Deprivation
[5] Gavrilova-Jordan,
Larisa, Thomas Price, 2007, Actions of
steroids in mitochondria
[6] Mellon,
Synthia, Lisa Griffin, Neurosteroids: biochemistry
and clinical significance
[7] Doodipala,
Reddy March 2004, Anticonvulsant activity of the testosterone-derived
neurosteroid 3α-androstanediol
[8] Aikey, Jeremy, John Nyby, et al, Dec 2002, Testosterone Rapidly Reduces
Anxiety in Male
House Mice (Mus musculus)
[9] Saad,
F, A. Aversa, et al, July 2013 Onset of effects of testosterone treatment and time
span until maximum
effects are achieved, this lists many of those benefits and a time line for
significant benefits. A list of from my
search of journal articles over a 15-year period with multiple journal links;
it is at http://healthfully.org/rc/id7.html.
[10] Kohtz Amy, Cheryl Frye, Dec 2011, Dissociating Behavioral,
Autonomic, and Neuroendocrine Effects of Androgen Steroids in Animal Models,
part of the Methods in Molecular Biology
[11]
Wojtal, Katarzyna, Michal Trojnar, et al, 2006, Endogenous neuroprotective factors:
neurosteroids
[12]
Wojtal, Katarzyna, Michal Trojnar, et al, 2006, Endogenous neuroprotective factors:
neurosteroids
[13] Cohen,
B. H., Gold, D. R., 2001, Cleve. Clin. J. Med.
68,
625 – 626, 629–642 Mitochondrial
cytopathy in adults: What we know so far
[14] Baulieu,
EE, Nov 1998, Neurosteroids: a novel
function on the brain
[15] Torro-Urrego, Luis Garcia-Segura, et al, June 2016, Testosterone Protects
Mitochondrial
Function and Regulates Neuroglobin Expression in Astrocytic Cells Exposed to
Glucose Deprivation
[16] Serra, Carlo, Nicolae Sandor, et al, Dec 2013, The Effects of Testosterone
Deprivation and Supplementation on Proteasomal and Autophagy Activity in the
Skeletal Muscle of the Male Mouse: Differential Effects on High-Androgen
Responder and Low-Androgen Responder Muscle Groups
[17] Wang, Xian-Jim, Tian-Yuan Xu, et al, May 2015, Castration
impairs erectile organ structure and function by inhibiting autophagy and
promoting apoptosis of corpus cavernosum smooth muscle cells in rats
[18] Laughlin,
Gail, Elizabeth Barrett-Conor, et al, Jan 2008, Low serum testosterone and mortality
in older men. This topic will be developed in #3,
which is on a combination of DHEA, testosterone, and IGF-1 levels.
[20] Luine, Victoria, Sept 2014, Estradiol and cognitive function: Past,
present and future
[21] Yi Jing,
Xue Tang, June 1995, Functional implication of autophagy in
steroid-secreting cells of the rat
[22] Li,
L., S. Sun, et al, June 2017, Effects of Estradiol on Autophagy and Nrf-2/ARE Signals
after Cerebral
Ischemia
[23] Holli, K, J. Isola, et al, sept 1998, Low biologic aggressiveness
in breast cancer in women using
hormone replacement therapy. Yes, in Europe, because they were using superior HRTs. In the US Prempro was and still is the
best-selling, though it is by far the worst. Prempor is equine estrogen combined
with medroxyprogesterone the worst of the progestins. For much more on the hatchet
job done by NIH with the WHI trial on behalf of
pharma. NIH knowingly chose Prempro, http://healthfully.org/rc/id2.html.
[24] Deng, L J Feng, et al., April
2010, The novel estrogen-induced
gene EIG121 regulates autophagy and promotes cell survival
under stress
[25] Guido, Carmela, Salvatorer Panza, et al, May 2012, Estrogen receptor beta
(ERβ) produces autophagy and necroptosis in human seminoma cell line through
the binding of the Sp1 on the phosphatase and tensin homolog deleted from
chromosome 10 (PTEN) promoter gene
[26] Li, L., S. Sun, et al, June 2017, Effects of Estradiol on Autophagy
and Nrf-2/ARE Signals after Cerebral
Ischemia
[27] Holli, K, J
Isola, et al, Sept 1998, Low biologic aggressiveness in breast
cancer in women using hormone replacement therapy
[28] Schierbeck, Louise, Lars Rejnmark, et al, October 2012, BMJ, Effect of hormone replacement therapy on cardiovascular events
in
recently postmenopausal women: randomised trial
[29] Studd, John, March 2010, Ten
reasons to be
happy about hormone replacement therapy: a guide for patients
[30] Di Saia, Philip, Wendy Brewster, et al, Dec 2000, Breast cancer survival and hormone
replacement therapy: a cohort analysis
[31]
The same logic probably applies to testosterone and prostate cancer. See discussion
of testosterone below.
[32] Judging
from repeated reports to me by women, a request for the natural hormones from a
compounding pharmacy will likely get a mixture of estrogens; E3 (estriol) which
is an antagonist of E2 (estradiol). I
presume it is on the computer program used for prescribing drugs--again I blame
bad pharma. The Natural HRT, estradiol plus progesterone is very likely the
best combination or with testosterone. I
favor on spotty evidence testosterone and instead of progesterone because of
its muscle maintaining effect. This
combination was used in Europe in the 1980s.
Also to be considered in prescribing is the reduced bioactivity with
age, thus to multiple by 2 the does adequate for a patient at 30 years to compensate
for one over 60 years. According to Goodman and Gilman, the absorption rate is
10% (the figure given for testosterone).
7. HERS, WHI, horse estrogen and MPA: “1992, Premarin became the number one
prescribed drug in the U.S.”[1] According to Wyeth (no owned by Merck) it
contained 10 estrogen hormones, supra.
The combination of horse estrogen and other steroids has never been
carefully tested for safety, and given that Prempro its combination with the
progestin medroxyprogesterone (MPA) was the leading HRT, the lacked convincing
clinical trials supported the need for a government ran trial, rather than by
its manufacturer. In the 1990s this was
provided, the HERS trial addressed the question of cardiovascular benefits in
high risk women, followed by a larger trial (WHI) for postmenopausal
women. However, the results could not be
extended to the many other formulas of HRT, but they were. The results of these
two trials were contrary
to many other prior trials using different products.[2] Given the press headlines and improper usage
of the results following the 2 trials, I can only conclude that this was a
well-orchestrated hatchet job of which there are many examples of that type of
media orchestration. This conclusion is
reinforced by the fact that in Europe the equine estrogen and its progestin
form (with MPA) were not widely prescribed, but the press the treatment and impact
upon the use of HRT were the same as in the US.
By now you must be tired of hearing me wave the flag of people
harmed.
The HERS study ran from 1993 until 1998 was of women
mean age of 67 who were at very high risk for coronary event (63% of women had
a risk higher than 20% over 10 years) and 19% were diabetic. The HERS trial
failed to find heart benefits for the post-menopausal women—contrary to a large
body of earlier studies. In an article
by a menopausal clinic trashing the HERS study, the authors pointed out that in
their clinic the average age was 53, 86% were younger than 60 years. The press
used the HERS study was used to
“prove” that estrogen conferred no heart benefits.[3] The same was done with the WHI (Women’s
Health Initiative) study, to which I have in detailed shown that it too was a
hatchet job—at /rhr.id19, supra. The
WHI (funded in 1991 and results released in 2002) looked at much more, and
though the risks and benefits of Prempro was a wash, the authors of the study
concluded that HRT should only be used to control significant unpleasant
effects of menopause, and only at the lowest dose for the shortest time. Over
and over again I find that abstracts and
conclusions of journal articles differ from the body of the article, and example
of such is the articles on the WHI.
Given early studies of Prempro and of MPA (medroxyprogesterone) several
critics knew that choice was an assault upon HRT.[4]
Excerpts from the Scientific
American article: I think that it
borders on a tragedy that Premarin and Provera [the 2 compounds in Prempro]
were chosen as the only HRT treatments [for the WHI Study]”. Another researcher
finds that Provera
[MPA]--and no other progestin--blocks the mechanisms that allow estrogen to
fight the brain's immune response to Alzheimer's…. Bruce S. McEwen Neuroendocrinologist of the Rockefeller University
is
unequivocally critical of the study: "I
think that it borders on a tragedy that Premarin and Provera [Prempro} were
chosen as the only HRT treatments.". . .
“With medroxyprogesterone [MPA] in Provera you are activating two
receptors involved with cell division in the breast," she says, "and
that's the culprit, not estrogen [for breast cancer].” Recent research
shows that Provera interferes
with estrogen's ability to prevent memory loss and dementia. “Estrogen is able to
protect neurons against toxic assaults that are associated with Alzheimer's
disease," notes Roberta Diaz Brinton, a neuroscientist at the University
of Southern California. . . she found “that Provera--and no other progestin--blocks
the mechanisms that allow estrogen to fight the brain's immune response to
Alzheimer's.” . . . ”This immune
response wears away at brain cells and causes them to leak neurotransmitters
such as glutamate, which overloads and kills neurons.” [5]
Is Nature ignorant of the
vital fact that Prempro contains no progesterone, but instead the artificial
progestogen
Provera [MPA]. The
other component is Premarin (conjugated estrogen), which is a very uncertain,
patent mixture of substances from the urine of pregnant mares…. [equine
estrogens] have crucially different effects.
Prempro is totally
unrepresentative of any other product used for HRT
purposes…. Much
of it was known before the NIH chose to use Prempro in its intended landmark
study. Using a study
of the effects of Prempro to attack the entire use
of HRT has, through needless fear, caused millions of women to forgo considerable
benefits of HRT using
better products. This point has
been repeatedly made by
endocrinologists. Why
does Nature
not know it?--END OF ARTICLE.[6]
The critics get their day in the journals, then the
details of their critique are forgotten, and the message by pharma is
remembered by over 90% of physicians and a greater percentage of the public,
“sex hormones have life-threatening risks”.
A 1999 study indicated that 38% of women between 50 and 74 years.[7] As of 2019, the number in that age group
using estradiol is under 5% for that age group; pharma has changed the practice
of medicine again. Among pharma’s tools
in addition to tobacco science are the clinical guidelines which form a barrier
to block what is in patient’s best interest.
Physicians will not recommend HRT; their patient asks for it. Guidelines
and their clinic’s standard of
treatment form a second effective hormonal barrier. Physicians who fall short
of the administrative
quotas are at risk of losing employment.
A physician who recommends estradiol for osteoporosis
or hot flash, and is taken to court for breast cancer, though natural estrogen
of progesterone lowers the rate, his attorney cannot argue that point because
expert opinion in the guidelines using the WHI and other studies claims HRT
promotes breast cancer and approves different medications. The Supreme Court
in the U.S. has ruled that
when there is a consensus of expert opinion, the defendant cannot argue that
the consensus is wrong. Giving advice in
the best interest of the patient has been buried by tobacco science,
guidelines, and the Supreme Court. The
silver spike is that often the insurance company do not list natural HRT in in
their formulary.
Add to this that pharma is very good at behavioral
control through perks, CME classes, handouts of articles, and establish a
religious like faith is their mantra, safe
and effective. Pharma has succeeded
in turning physicians into pill pusher.
Few doctors are willing to be outsiders in our age of miracle
drugs. For very possible the best 5-page
account of why doctors are pill pushers, and it is sympathetic to their
situation go to http://healthfully.org/rep/id11.html.
This work
on CAWD and
autophagy has taken me full circle for I have come back to my early extensive
review of the sex hormones done between 2004 and 2006 for https://healthfully.org/fhr and
/malehormones, these results of my first review of the literature gave me my
first strongly supported example of how pharma with its lapdogs the FDA and
corporate media were promoting profits over health, while selling their results
as protecting the public and promoting health.
The early studies on the benefits of HRT were not wrong, not overturned
by a studies of Prempro (horse estrogen and medroxyprogesterone).[8] I had listened to Prof. Robert Langer explain
to a large audience in 2003 at UCSD’s medical school that the results of the
WHI (Women’s Health Initiative using Prempro) couldn’t be extended to other
formulas of HRT. My review of the topics
confirmed his statements. The
consequences of replacing what works with what doesn’t has a very personal
negative my mother and my father concerning their health and quality of life
and convinced me of the importance of treating low testosterone (#14).
And it is
not only
estrogen and some of the other steroid hormones[9] that turns up autophagy
and lowers the risk for cancer. The
major Harvard’s Nurses’ Study[10] found that daily aspirin
very significantly increased the survival of breast cancer for those who
weren’t stage 4. Both estradiol and
aspirin (2:5, 5) promote
autophagy,[11] thus apoptosis its other
benefits.[12] I was started on 8 aspirin a day (325 mg
enteric coated in 1992 to treat chronic back pain). After finding out in 1993
based on a
University of Toronto population study, that aspirin reduced the risk by over
50% for colon cancer, I continued with 1 to 2 aspirin up to this present
day—now uncoated because of low absorption rate for the coated aspirin which
takes 8 hours for peak level with a meal.
The criticisms
are
buried by time: consider the evolution
of the Wikipedia article on the Women’s Health Initiative study (WHI is the
second major piece of tobacco science); the article has slowly evolved to
mirror the teachings fed doctors and public about HRT. The same crapola
is repeated in the Wikipedia article on HRT, which misuses the WHI trial.[13] The current Wikipedia article for the WHI
study makes no mention of equine estrogen or that medroxyprogesterone blocks
some of the benefits of estrogen.[14] The early critics like Prof. Langer are
ignored, as too all the earlier studies which supported a much different
outcome. Over and over again I read in
journals how the WHI study with a budget of $625 million his the gold standard.[15] So what are their figures for WHI? Note,
AR is events per 10,000 person
years. Prempro increased coronary heart
events (1.24, AR +6), strokes (1.31 AR +8), pulmonary embolism (2.13 AR +10),
breast cancer (1.24 AR +8), dementia, (2.05),* and gallbladder disease (1.59)*
which are contrary to earlier studies that excluded Prempro. The plus side for
Prempro balanced out those
negative effects in that the total mortality dropped slightly (0.98, AR -1),
hip fractures (0.67, AR-6), all factures (0.76, AR -47), colorectal cancer
(0.66, AR -7), endometrial cancer (0.81, AR -1), diabetes (0.70).* The asterisk
is for those which there are no
AR figure. Since the study 2002, both
type 2 diabetes and dementia have over doubled, thus AR figures for Prempro
would clearly justify its usage and that of all the other HRTs. Need I again
comment about how Wikipedia
relies upon KOLs? And what is echoed by
Wikipedia is supported by sources that all receive funds from pharma and others
relying on expert opinion.[16] Unfortunately, most readers assume that
hormones are bad, I hope you who don’t know better will hear the wake up bells
of Marcia Angell and Peter Gotzsche.[17]
8. Osteoporosis and estrogen;

General structure of bisphosphonate

As one doctor
told me
in 2005 commenting on the WHI: “There
goes the effective treatment for osteoporosis.”
This is a major health disaster because a good treatment has been
replaced by one which long-term does more harm than good. Having eliminated
the competition of HRT, the
2001 numbers for fractures in postmenopausal women have more than double. “The
lifetime risk of symptomatic fracture for a 50‐year‐old Caucasian man in the UK
has been estimated to be 2% for the forearm, 2% for the vertebra and 3% for the
hip, whereas the corresponding figures for a 50‐year‐old woman are 13%, 11%,
and 14%, respectively.” [18] Osteoblasts have both estrogen and
testosterone receptors for a reason. Again
we have pharma orchestrating a stampede for profits.
“The
female sex estrogen
deficiency following menopause or surgical
removal of the ovaries is correlated with a rapid
reduction in bone mineral density, while in men, a decrease in testosterone
levels has a comparable (but less pronounced) effect” [19] “Osteoporosis
and
osteoporotic fractures are generally considered to mainly affect older
postmenopausal women, but up to 20% of symptomatic vertebral fractures and 30%
of hip fractures occur in men. . .
. One of the major secondary causes of osteoporosis in men is hypogonadism”[20] “Male
patients affected by rheumatoid arthritis[21]
have been shown to possess low serum testosterone”
[22] and a similar finding for osteoarthritis. Compared to women, the decline in men is gradual.[23] These declines in men and women are more than
mere association, a wide variety of evidence shows the relationship to be
causal.
One reason
for the
assault upon the estrogen in is a class of drugs known as bisphosphonates. This
assault extend to DHEA, since it too
lowers the risk for osteoporosis.[24][25] Progesterone also is effective in preventing
osteoporosis. Progesterone also has been
proven very effective at preventing osteoporosis and reversing it.[26] Very possible there is a similar to the
results of the InCHIANTI study, the combination of hormones is better than just
estradiol. Most of the biological
pathways involve several hormones—a fine tuning of the regulatory process. Research
has shown that estradiol doesn’t promote bone remodeling, rather
it slows the loss of bone (calcium)
and it is the progesterone that promotes calcium absorption; they function as a team. For men it is testosterone and estradiol that
function as a team (low testosterone entail low estradiol, since some of the
testosterone is converted to estradiol).
But first let us look at what pharma has done based upon hormonal
hysteria, the bisphosphonate treatment.
Pharma replaced
nature’s way with bisphosphonate, and then showed it increased bone
density—ultimately for marketing by use of the surrogate endpoint of density
and a very modest reduction short-term in fractures (need I again mention fraud
in trials?). [27] Bisphosphonates
consist of 2 polar phosphate groups, which are absorbed by the bones. But this
group--as one should expect--doesn’t function as well as calcium compounds. They
don’t make the bones stronger, just
denser.
Density doesn’t
equate
either to less brittle. Children for example have less than half the density of
adults. At age 3 the average male TBLH (total
body less head) BMD in grams per/cm2 is 0.3; at 5 0.46; at 9 0.63,
15 0.85, and 18 years 0,95; and females at 18 years is 0.75.[28] By the age of 80 the
average is about the same as an 8 year old.
But given the great difference in frequencies of fracture, the association
of density with fracture fails to capture the brittleness of the senior’s
bones. Moreover, bone mass is controlled
by a hemostatic system that tends to return to a set point after any
perturbation.[29]
The
very mechanism by which bisphosphonates modestly contributes to bone density
explains why their biased claim of benefit is slim, and gets worse the longer
the study is run.[30] “It is now clear that
bisphosphonates inhibit bone resorption by being selectively taken up and
adsorbed to mineral surfaces in bone, where they interfere with the action of
the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts
and interfere with specific biochemical processes.” [31] “The inhibition of protein phenolation and
the disruption of the function of these key regulatory proteins explains the
loss of osteoclast activity and induction of apoptosis.” [32] By the bisphosphonates increasing apoptosis of
osteoblasts rate increases the overall decline in osteoclast activity results
in brittle bones. The fix isn’t what
guidelines call for, that of adding phosphate groups to the bone, or other
foreign compounds.
There
is evidence from animal studies that with prolonged alendronate [Fosamax] use,
bones become more brittle and susceptible to fracture. Unfortunately, it is
currently unknown at what point that occurs in people. . . . When used
for secondary prevention
of fractures
(subsequent fractures), the number of women who would need to be treated with
alendronate for five years to prevent one hip fracture was 100. . . . Severe ulcers
in the esophagus is a well-documented hazard.[33] Atrial fibrillation, an irregular
and rapid heartbeat, is a newly
recognized risk being investigated by the Food and Drug Administration. . .
. Osteonecrosis of the jaw (destruction
of the jaw bone) is a very serious complication. . . .
Lastly, incapacitating bone, muscle and joint pain is another known
hazardous side effect of bisphosphonates.[34] And the best treatment, based on the
WHI study is the main justification the warning against estrogen: “Furthermore,
the ACP recommended against
using menopausal estrogen therapy or menopausal estrogen plus progestogen
therapy or raloxifene (Evista) for the treatment of osteoporosis in women. This
was graded as a strong recommendation with moderate-quality evidence.” [35]
We
have another case of good drugs off-patent (hormones) being replaced by drug
(bisphosphonates) which are worse than nothing at all. If only the governments
would open up their
data banks so that we can now how much worse real world patients are doing on
the patented drug.
Has anything changed?
current guidelines:
“The
American College of Physicians (ACP) has recommended in an evidence-based clinical
practice guideline(annals.org)
that physicians offer pharmacologic therapy with a bisphosphonate --
alendronate (Fosamax), risedronate (Actonel, Atelvia) or zoledronic acid
(Reclast) -- or the biologic agent denosumab (Prolia) to reduce the risk for
hip and vertebral fractures in women who have known osteoporosis.[36]
The situation
gets
complex, and as stated in the 2nd paragraph of this section, relying
upon the lead of the InCHIANTI Study, the combination of hormones is better
than one. Important results are submerged
in the sea of journal articles.[37] it isn’t only estradiol that contributes to a
positive bone remodeling but the combination with progesterone. Estradiol promotes
bone reabsorption and the
same for testosterone. The supplement of
estradiol by itself diminishes the rate of calcium absorption from the bones
and progesterone promotes the utilization of calcium to build new bones. Testosterone
works with estradiol in men to
halt the loss of bone calcium.[38]
It took me
15 years of
researching estradiol and testosterone, from 2004 until 2015 to find out about
the current combination. Moreover, I had read the Goodman and Gilman 1981
Edition of The Pharmacological Basis of Therapeutic
in the early 1980s and its role in promoting “last only 9
to 14 months” and the next paragraph “only 25% of women postmenopausal patients
develop osteoporosis and treatment with calcium salts is as or more effective
than routine prophylactic use of estrogen is more difficult to justify” P.
1431. However, the use of calcium
supplement in quality studies has been shown to be ineffective because it has
no effect upon the hormone control of remodeling. As for duration of benefit,
it is
continuous. The roots for the Prempro
attack upon HRT goes back to this book and undoubtedly before “However all
estrogenic materials can cause the more serious cardiovascular and perhaps
tumorigenic effects” P 1428. No mention
is made of the role of progesterone’s role in remodeling. It should have
been highlighted in Wikipedia,
and mentioned in a number of journal articles on osteoporosis or the benefits
of HRT in the introduction or discussion section.
Reading extensive
hundreds of journal articles on the 2 major sex hormones and other related
hormones, I only came across the statements of their synergistic effect on bone
remodeling. Then after 15 years, I
became aware that estradiol slows the resorption of calcium of the slowing of
the loss of calcium nor had I read that progesterone increase in the rate of
absorption for building bones. Nor in my
preparation for a review of progesterone did I find references to osteoporosis;
its calcium references were about calcium signalling.
Kinetic
and histomorphometric data suggest that bone formation and resorption are
closely linked (3, 4). Increased resorption, which occurs after the menopause, will
not cause a net loss of bone if formation is
equally increased. Studies of bone
histology suggest that bone formation in postmenopausal women is not increased
but is inappropriately “normal” or low (5, 6). Estrogen treatment is associated
with decreased resorption and with no change or a slight decrease in formation
(5, 7). The long term net response to estrogen therapy appears to be decreased remodeling
and the creation of a relatively
inactive bone mass (5–7). Despite Albright's assumption that estrogen
deficiency caused decreased bone formation, it is now clear that estrogen's
predominant effect is to decrease bone resorption.” [39] “Fuller
Albright's observation that women developed osteoporosis after, but rarely
before the menopause, led him to assert that osteoporosis was caused by
hormonal changes around the time of the climacteric (1). Although his first
clinical trial tested progesterone and testosterone, as well as estrogen
treatment, Albright believed that it was estrogen deficiency that resulted in
decreased bone formation and caused osteoporosis, “a condition in which the
osteoblasts were primarily deficient in laying down osteoid tissue” (2).” [40]
The combination of the two hormones
work
together for healthy bones, using just estradiol would result in the
accumulation of older osteoblasts. Something
is very wrong when role of progesterone is left to obscurity, thus the use of
estradiol is not enhanced. I wonder who
benefits from ignoring the role of progesterone? This follows the usual pattern
of tobacco
ethics.[41]
These studies
of the
steroids, that progesterone plays, as to bone health, is one of several significant
healthful roles. We shall find out
another major piece to the puzzle concerning bone formation and remodeling is
the replacement of collagen (4:4),
to which low
ascorbic acid and MTDD are involved in the pathogenic processes. Evolution has
fined tuned the process of
remodeling, and the closer we can follow its path the healthier we will be
(pharma eat your marketing hat).[42]
I take very personal what happened
to my
mother who had the age of 91 had her 3rd bone break. She spent two
days on the floor of her
apartment, until someone heard her banging on the floor and came to
investigate. The next two years at great
expense she spent on her back unable to move.
Finally, the friend of old people, phenomena, in three days ended her
low quality life.
Fosamax, which she took for and
prior
Aredia for a decade makes bones brittle; it doesn’t promote bone
remodeling. She is one who will take
every pill her doctor gives; however, she stopped taking Fosamax 4 years before
her hip break because of side effects.
She did go back on to Aredia (pamidronic acid) for that too caused
nausea. No, I am not angry at pharma,
for the companies play by the capitalist rule of profits before people.
I am a Benthamite, a utilitarian
and thus
known that the ideal system to rational guide behavior is to have each person
try to maximize the well-being of all people.
The problem isn’t the people, but what shapes their behavior. My
roots go back to Plato as voiced[43]
in his The Republic and Epicurus’
maxims.
9. Epidemic of osteoporosis and osteoarthritis: What is driving the bone on bone joints and
bone breaks? One part, as by now you
expect, is the B-4 and the lack thereof in LSPs of those conditions. Down-stream
is the hormone levels of the
elderly,[44]
the rancid, oxidized fats in cell membranes, delayed replacement of collagen,
problem a sensitivity to uric acid, medications, and others whom I have yet to
uncover. The role of drugs founds some light in
a
Wikipedia list. I have been warning for
about 12 years about protein pump inhibitors, but their list is much longer.
Certain
medications have been associated with an increase in osteoporosis risk; only
glucocorticosteroids and anticonvulsants are classically associated, but
evidence is emerging with regard to other drugs.
The two are additive, the chemicals
and the
B-4 and all that follows from B4, such as the folding of collagen.
The low hormones are a CC to the RRA and RATP that is causing the epidemic
of arthritis; “there are over 100 types of arthritis. . . . [i]n the United
States more than 20%
have a type of arthritis.”[46] “Population studies indicate the extremely
high prevalence of OA (over the age of 70 up to 90% of the [female] population
have some radiological evidence of OA)”.[47] “Free and serum
testosterone levels were significantly lower in the RA males than in either the
AS [ankylosing spondylitis] group or the healthy controls”[48]
Moreover, improvements have been shown with
the administration of testosterone.
Similar results for estrogen and progesterone. With our high sugar diet
and thus the B-4,
the decline in sex hormones that has steadily increased over the last 100 years
(graph #4)
and I assume the same for testosterone’s sister the
estrogens, we have over two-thirds the population above 70 experience
joint pains and worse. We have another
class of illness that is virtually unknown for the LSPs, and was 200 years ago only
a condition of affluence.
[1]
Vance, Dwight, 2007, Premarin: The
intriguing history of a controversial drug
[3]
Gambacciani, Marco, Guiseppe Rosano, et al, Aug 2002 Clinical relevance of the HERS
trial
[4]
Premarin came on the market in 1942, and name comes from mare, for which equine
estrogen is derived from mare urine. #
decades later medroxyprogesterone (Provera) was added and the combo called
“Prempro”, conjugated estrogen and MPA.
[5] Dennis Walkins, October 2003, Scientific American, Hormone Hysteria?
[6] Michaels, ANNA, Sept 2010. My link to the original article goes to a
different page in Nature, an article claiming that pharma’s ghost writers have
downplayed risks of HRT, at http://www.nature.com/news/2010/100907/full/news.2010.453.html#comment-id-13486. A business
switch in articles made by the editor of Nature with approval of pharma. Though
the industry attacks HRT, those that
manufacture it won’t pull it from the market, though they all too often come
out with new version that is too low a dose or in other ways minimally
effective, such as enteric coated low-dose aspirin.
It is all governed by profits.
[7] Keating,
Nancy, Paul Cleary, et al, April 1999, Use
of hormone replacement therapy by postmenopausal women in the United States
[8] A
bit of history: “Beginning in 1975,
studies began to show that without a progestogen, unopposed estrogen therapy
with Premarin resulted in an 8-fold increased risk of endometrial cancer, eventually causing sales of
Premarin to plummet.[52]
It was recognized in the early 1980s that the addition of a progestogen to
estrogen reduced this risk to the endometrium.[52]
This led to the development of combined estrogen–progestogen therapy, most
commonly with a combination of conjugated equine estrogen (Premarin) and
medroxyprogesterone (Provera).[52]
“ Wiki HRT April 2019. Again,
apply the results of an increase in
endometrial cancer to horse estrogen, the results don’t extend to
estradiol. I
am not aware of an association with estradiol.
[9] In
their sections, DHEA and Testosterone lower the rates of cancer, which is what
to be expected given their upregulation of autophagy. What of pregnenolone, progesterone, and IGF-1
[10] Holmes, Michelle,
Wendy Chen et al (4 women0 March
2010, Aspirin intake and survival after breast cancer
[11] Din, Farhat, Asta Valandiute, et al, June
2012, Aspirin Inhibits
mTOR Signaling,
Activates AMP-Activated Protein Kinase, and Induces Autophagy in Colorectal
Cancer Cells
[12] Pietrocola, Federico, Francesca Castoldi, et al, Feb 2018, Aspirin recapitulates
features of caloric
restriction. Caloric restriction
lowers glucose and insulin level and increases autophagy and lippolysis.
[13]
Wiki hormone replacement therapy April 2019, and
[14] Adams,
Michael, Thomas Registor, et al, Feb 1996, Medroxyprogesterone Acetate Antagonizes
Inhibitory Effects of Conjugated Equine Estrogens on Coronary Artery
Atherosclerosis “Although
estrogen replacement therapy is associated with reduced risk of coronary heart
disease and reduced extent of coronary artery atherosclerosis,. . . . Treatment
with CEE alone resulted in atherosclerosis extent that was reduced 72% relative
to untreated (estrogen-deficient) controls (P<.004). . . .
MPA-associated antagonism. . . . oral CEE [continuous equine estrogen] inhibits
the initiation and progression of coronary artery atherosclerosis and that
continuously administered oral MPA antagonizes this athero-protective effect.”
[15]
Particularly annoying I s the calm of reward from the WHI study “A 2014
analysis calculated a net economic return on investment of $37.1 billion for
the estrogen-plus-progestin arm of the study's hormone trial alone, providing a
strong case for the continued use of this variety of large, publicly funded
population study.” Wiki WHI April 2014, in Roth, Joshua, Ruth Etzioni, et al,
May 2014, Economic Return From the
Women’s Health Initiative Estrogen Plus Progestin Clinical Trial, A Modeling
Study The over 100 million women harmed in the US alone over the
last 15 years by not taking HRT is written up as a benefit using WHI tobacco
science. Sad, the crap we are fed as
good, like the lead compound that once was frequently added to wine until the
1700s to improve its flavor. Marketing
needs to be barred from science to prevent a sweat words hiding harm.
[16]
“Evidence to support long term use however is poor.” Quote from Wikipedia based
on the Position of the North American Menopause Society. March 2012 The 2012 Hormone
Therapy Position Statement of The North American Menopause Society. They
relied on the WHI study with no mention Prempro for their series of warning
concerning risks versus limited benefits.
[17]
If I was a god, I would castrate every surgeon who in doing a hysterectomy has
taken sound ovaries—only joking. This
would be divine Judeo justice. PS, I am
a utilitarian and therefor retribution is immoral.
[18]
Francis, RM, Dec 2001, The effects of testosterone
on osteoporosis in men (a seminal review article)
[19] Wiki,
Osteoporosis, April, 2019. I do not
recall factures in women being a major concern in the 1950s and 60s.
[20] Tuck, S, R Francis, 2009, in Advances in the Management of Testosterone
Deficiency Vol. 37, pp. 123-133 Testosterone,
Bone and Osteoporosis
[21] Cutolo, Maurizio, Enrico Balleari, et al Oct 1998, Sex hormone status of male patients with rheumatoid arthritis: evidence
of low serum concentrations of testosterone at baseline and after human
chorionic gonadotropin stimulation
[22] Cutolo, Maurizio, Enrico Balleari, et al Oct 1998, Sex hormone status of male patients with rheumatoid arthritis: evidence
of low serum concentrations of testosterone at baseline and after human
chorionic gonadotropin stimulation
[23] The
putative heart benefit of estrogen evaporates with the LSPs in that the elderly
of both sexes are CVD free. See Taubes The
case against sugar, where he describes the first case of a Nigerian
with CVD. He was educated in England in
law and became in Nigeria a Supreme Court Justice; thus Western diet caused his
CVD.
[24]
Scott, A, K. Higdon, et al, Jan 2001 The prevention of
osteoporotic progression by means of steroid loaded TCPL drug delivery
systems. “that DHEA
may possibly be used in postmenopausal patients to reduce osteoporotic
progression.”
[25] Gordon, Catherine, Julie Glowacki, Aug 1999, DHEA and
the skeleton (through the ages)
[26]
Lee, JR, Aug 1991 Is
natural progesterone the missing
link in osteoporosis prevention and treatment?
[28] Liu Junjting, Liang Wang
et al, May 2017, Bone mineral density
reference standards for Chinese children aged 3–18: cross-sectional results of
the 2013–2015 China Child and Adolescent Cardiovascular Health (CCACH) Study.
In the study there were figures for the
US NHANES study
[29]
Gafni, Rachel, Jeffrey Barron, March 2007, Childhood Bone Mass Acquisition and Peak Bone
Mass
May Not Be Important Determinants of Bone Mass in Late Adulthood
[30] For
those who wish to know more about the fractured
clinical trial system, I recommend Prof. Ben Goldacre’s Bad Pharma. ”Ben Goldacre
is a founder of the campaign and its [AllTrials] most public spokesperson. In
2016 he participated in the launch of the OpenTrials database. AllTrials is an
international initiative of Bad Science, BMJ, Centre for
Evidence-based Medicine, Cochrane
Collaboration, James
Lind Initiative, PLOS and Sense About
Science and is
being led in the US by Sense About Science USA, Dartmouth’s
Geisel School
of Medicine and the
Dartmouth Institute for Health Policy & Clinical
Practice”.. , , , As of
May 2017, The AllTrials petition has been signed by
90,282 people and 721 organisations. Wiki AllTrials,
April, 2019.
[31]
Russell, RG, July
2011, Bisphosphonate: the first 40
years
[32]
Russell, RG, MJ Rogers, July 1999. Bisphosphonates:
from the laboratory to the clinic and back again
[36] AFFP (American
Academy of Family Physicians) endorses ACP Guidelines on treating Osteoporosis, May
11, 2017 article, at aafp.org.
[37]
Over and over again I find evidence that should be broadcast lost in that sea,
such as very high dose of aspirin reversing T2DM, cholesterol is produced at
night, therefore, why take a stain or niacin during the day? Enteric coated
aspirin takes 8 hours for peak
serum level, compared to under an hour for uncoated aspirin, and on and on as
you can tell by my digressions.
[38] Falahati-Nini, Alireza, B. Riggs, et al, Dec 2000, Relative contributions
of testosterone and
estrogen in regulating bone resorption and formation in normal elderly men. FULL
“We
conclude that in aging men, E is the dominant sex steroid regulating bone
resorption, whereas both E and T are important in maintaining bone formation.”
[39]
Lee, JR, Aug 1991, Is
natural progesterone the missing
link in osteoporosis prevention and treatment?
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