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Recommended-Book-jk-fructose-mitochondria-sickness
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6:2 HORMONAL HEALTH
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SECTION 6—2-Sex
and related hormones, fine
tunes autophagy 6/9/19
 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
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 their
functions in the mitochondria promotes a weakening of the immune system and
thus to promote the infectious concequense which is what the LSPs in the
pre-electric world die from. 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, androgens, and their structurally related steroids:
of these I have reviewed in depth the
literature on the sex hormones, pregnenolone,[1]
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. [2] They are synthesized in
the gonads, adrenal cortex, and some other tissues including in the brain by the
glial cells.[3] Because pharma frames the topic, their
function as neurosteroids has been burried.[4]
“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.”
[5] 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.[6] 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.[7] There is much more to the sex steroids then
the development of sexual characteristics.[8] 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).[9]
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.[10] I had for 15 years settled for association of
the health benefits of these 3 hormones[11]
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.[12]
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).[13]
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[14] 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.[15] [16] 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]
“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.
[2]
Kliewer, Steven, John Moore, et al, Jan 1998, An
Orphan Nuclear
Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway
[3]
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.
[4]
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.
[5]
Wiki, neurosteroids, Sept 2019
[6] 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.”
[7] 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.
[8] Many
of the sex steroids are neurosteroids and some act as positive allosteric
modulators of GABA receptors.
[9] 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.
[10] 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.
[10]
As usual I must cherry pick the evidence based upon my understanding of how
cells function, pharma functions, and evolution.
[11]
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.
[12] 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.
[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
[14] 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.
[15] 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.
[16]
Vasconsuelo, Andrea, Lucia Pronsato, et al, Nov 2011,
Role of 17β-estradiol and testosterone in
apoptosis
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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.
UTI, NFALD,
and venus thrombosis for E2, look them up
for TTT More from the two rc/ articles
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.
[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.
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[1] 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. “ [2] [3] It has been shown to following a cerebral
ischemic event to inhibit apoptosis by increasing autophagic cellular repair.[4] “It is also protective of mammary epithelial
cells (MEC) by a tightly controlled balance be reparative autophagy and apoptosis.”
[5] 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.[6]
Our study reveals a unique mechanism through which ERβ/PTEN signaling
induces cell death in TCAM2 by autophagy and necroptosis[7]
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.” [8]
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.”[9] 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).[10]
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: [11]
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). [12]
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).[13] 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.[14]
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.
[2] Luine, Victoria, Sept 2014, Estradiol and cognitive function: Past,
present and future
[3] Yi Jing,
Xue Tang, June 1995, Functional implication of autophagy in
steroid-secreting cells of the rat
[4] Li,
L., S. Sun, et al, June 2017, Effects of Estradiol on Autophagy and Nrf-2/ARE Signals
after Cerebral
Ischemia
[5] 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.
[6] Deng, L J Feng, et al., April
2010, The novel estrogen-induced
gene EIG121 regulates autophagy and promotes cell survival
under stress
[7] 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
[8] Li, L., S. Sun, et al, June 2017, Effects of Estradiol on Autophagy
and Nrf-2/ARE Signals after Cerebral
Ischemia
[9] Holli, K, J
Isola, et al, Sept 1998, Low biologic aggressiveness in breast
cancer in women using hormone replacement therapy
[10] Schierbeck, Louise, Lars Rejnmark, et al, October 2012, BMJ, Effect of hormone replacement therapy on cardiovascular events
in
recently postmenopausal women: randomised trial
[11] Studd, John, March 2010, Ten
reasons to be
happy about hormone replacement therapy: a guide for patients
[12] Di Saia, Philip, Wendy Brewster, et al, Dec 2000, Breast cancer survival and hormone
replacement therapy: a cohort analysis
[13]
The same logic probably applies to testosterone and prostate cancer. See discussion
of testosterone below.
[14] 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]
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