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?
[40] Prior, JC, May 1990, in Oxford
Academic, Endocrine Reviews Progesterone as a Bone-Trophic Hormone
[41]
In Wikipedia “Progesterone also has a role in skin elasticity and bone
strength, in respiration, . . . “ Wiki,
progesterone, 5/19. This fails to inform
what its role is, or that it ought to be used for treating osteoporosis, more
of the usual pattern. When my mother got
the ineffective Fosamax for osteoporosis in the 1990s, it wasn’t the doctor’s
fault but that of tobacco ethics shaping treatments.
[42]
The very unnatural Prempro, was in the WHI study positive for prevention of
joint-bone problems, but not for CVD and cancers, etc. Natural is almost always
the best treatment,
but unneeded for LSPs.
[43]
In his day dialogues and works such as The
Histories by Herodotus were read
in installments to an audience, as too poems.
[44] Insightful would be hormonal measurements of the elderly
of
the LSPs, fracture rates, and bone density.
[45]
Wiki osteoporosis May 2019.
[46]
Wiki, arthritis, May 2019
[47]
Spector Tim, Giles Campion, June 1989, Generalised
osteoarthritis: a hormonally mediated disease.
This article starts with a detailed recount of the early published
clinical cases, then progresses to population studies, followed by experimental
studies,
[48] Spector, T.D, William Ollier, et al, March 1989, Free and
serum
testosterone levels in 276 males: A comparative study of rheumatoid arthritis,
ankylosing spondylitis and healthy controls
18. Progesterone and progesterins
From Wikipedia, (https://en.wikipedia.org/wiki/Progesterone) the labels for each of
the steroids has been lost in copying
It is synthesized from pregnenolone, and has a list of functions
similar to that of the big 3 discussed, testosterone, estradiol, and DHEA. Along
with estrogen, progesterone has many of
the functions that regulate female reproductive organs. It is the major progestogen
(P4) of which
there are at least 8. Most of its
functions occur like with pregnenolone in the endoplasmic reticulum. Besides
it role in sexual development and
function, progesterone has many roles affecting the brain and nervous system
(neurosteroid), bone strength, skin elasticity, gall-bladder activity, insulin,
blood clotting, antioxidant properties, epidermal growth factor (EGF-1), and
inflammation. Its roles in autophagy
effects the uterus, brain, mammary gland, and promotes stimulation of apoptosis
in response to cancers of several tissue type including skin (melanoma), liver
uterus, breast. Given all these
functions and the well-established benefits of most formulations of HRT, this
makes a strong argument for its inclusion with estradiol in HRT, even for women
without a uterus. Note: I
have failed to find literature on its function for the male, and
therefore, I cannot comment on its inclusion with testosterone for hypogonadism. Given its metabolism to other
active
steroids, this undoubtedly accounts in part for many of progesterone’s many
functions.
19. Neurosteroid summary: Neurosteroids are synthesized from cholesterol, and are either
endogenous or exogenous steroids that rapidly alter neuronal activity. Of particular
interest are those made in the
brain or endocrine glands and that there are in the brain receptors for them.
“Some the steroids affect gene expression.; some are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate.
. . . Neurosteroids increase both synaptic and
tonic inhibition. They are endogenous regulators of seizure susceptibility,
anxiety, and stress” [1]
Given
the number of neurosteroids, their interactions, the use of
animal models, makes a detailed analysis of their activities and behavioral
effects a long way off. Nevertheless,
positive results have been observed among those with low levels through their
restoration to a youthful level for testosterone, DHEA, estradiol, and
pregnenolone, and others.
20. Testosterone, estradiol, and T2D: so what
is the evidence supporting a prophylactic role of the hormones in preventing the
spectrum of hyperglycemia, IR, and T2DM?
Given the role of fructation in CAWD, these steroids would in part act
to lower risks through lowering IR and T2DM.
Testosterone: The results of the NHANES Study won’t go
away in proper studies:
RESULTS—In
multivariable models adjusted for age,
race/ethnicity, and adiposity, men in the first tertile [lowest] of free testosterone
level were four times more likely to have
prevalent diabetes compared with men in the third tertile [highest] (odds
ratio 4.12 [95% CI 1.25–13.55]). Similarly, men in the first tertile of bioavailable
testosterone also were
approximately four times as likely to have prevalent diabetes compared with men
in the third tertile (3.93 [1.39–11.13]). . . . CONCLUSIONS—Low
free and bioavailable testosterone concentrations in the normal range were associated
with diabetes,
independent of adiposity. These data suggest that low androgen levels may be a
risk factor for diabetes in men.[2]
This
association in NHANES III is consistent with other population studies and
various mechanism that show mitochondrial and cyto-protection for sex steriods.[3]
NHANES is a frequently quoted study,
done in
phases beginning in 1971 through a program of the Center for Disease Control,
and continuing through to 2016, and possible currently.[4]
The results of the NHANES III support the role of testosterone in
lowering blood glucose and reducing MTDD.
Other studies had similar findings as to HRT and rate of T2DM. According to the MTTD root
cause theory I am presenting, and fitting in with TOFI, and lean people
developing T2DM, the association might be based on MTTD.
B. Estradiol:
In a controlled studied of postmenopausal women
it was shown that subsequent estradiol very significantly reduced the risk of
developing T2DM, and given its high rate among senior women, above 30% and its
very significant effect upon quality of life and longevity, this number along would
place estradiol first among healthful supplements (yes, supplements since it is
natural to the body.)
Type 2 diabetes developed in 60 patients
during the follow-up period, which is the equivalent of 22 cases per 1,000
women-years. In the “hormones nonusers” group, diabetes developed in 10% (54 of
529 women; equivalent of 26.5 cases/1,000 women-years), whereas in the
“hormones users” group, diabetes developed in 4.16% (6 of 144 women; equivalent
of 12.1 cases/1,000 women-years). Transdermal 17-β-estradiol emerged as a
treatment that significantly reduced the risk of developing diabetes (RR 2.19,
95% CI 1.79–3.56; P = 0.006). Conclusion: Our results
suggest a significant reduction in the incidence of type 2 diabetes in our
population of non-obese, healthy postmenopausal women who used transdermal
17-β-estradiol. This could suggest that, in some women, the estrogen deficiency
that occurs after menopause could represent a fundamental step in the process
of diabetogenesis.[5]
The
same has been found in the seminal article on natural HRT as to the benefits of
all the neurosteroids
Merely turning on a gene or starting a regulatory process calls
into action a wide variety of systems which adjust the process to maximize
benefits. The sex steroids are part of
complex systems of which they play major roles.
There are of 5 classes of steroids:
cholestanes (cholesterol), cholanes (cholic acid), pregnanes
progesterone), androstanes (testosterone), and estranes (estradiol). Among their
many actions there has been found
to be receptors in the MTD. In the 2007
article Actions of steroids in mitochondria:
Their
functions in the MTD brings me back to the question of why steroids levels drop
in the 6th decade and thereafter; its evolutionary advantage is the
elimination of the elderly burden. Their
functions in the MTD in part explains why HRT improves quality of life. The
youthful levels of the sex steroids
promote health, but in the 6th decade that function has been
compromised. Given the number of studies
which demonstrate their benefits, their action in the MTD, the lack of
prescribing HRT is a major CC for CAWD—end of case.
[1]
Ruddy Doodipala, 2010, Chapt 8 Neurosteroids: endogenous role in the human brain and
therapeutic potential in Progress in
Brain Research, pg. 113
[2] Selvin,
Elizabeth, Feinleib Manning, et al, Feb 2007 Androgens and Diabetes in Men: results from the Third National Health and
Nutrition Examination Survey (NHANES III)
[3] Gavrilova-Jordan,
Larisa, Thomas Price, 2007, Actions of
steroids in mitochondria
[4] It
is part of the National Health and Nutrition Examination Survey, and is at https://www.cdc.gov/nchs/nhanes/index.htm Findings have been frequently referenced as
established figures of the US population such as for NAFLD.
[5] Rossio,
Rosario, Giorgia Origiliani et al, Mar 2004 Transdermal 17-β-Estradiol and Risk
of
Developing Type 2 Diabetes in a Population of Healthy, Non-obese Postmenopausal
Women
10.
My historical note
on hormones: I
had around 1963 came to believe that senior
men should take testosterone to improve quality of life. This observation of
elderly men was
consistent with a recent Scientific American article on testosterone, and the
lack of negative information from the media.
By 1989 I was considered buying over-the-counter androgens. After a review
of the literature in 2001, I
bought 2 different steroids, 4-androstene-3,17-diol (sold over-the-counter
until about 2005) and DHEA. The
4-androstene was to bitter to take sublingually; however, DHEA had a mild amine
test. Suspecting government regulation
by 2003 I had stocked piled 125 grams of DHEA powder from Bulk Nutrition--as of
2020 it is still over-the-counter. I
took sublingually to avoid first pass liver metabolism, which occurs when absorbed
from the intestines. The 4-androstene I
dissolved in ethanol and used as a spray.
I had bought on 10 grams, and didn’t restock.
In 2004, having
low
testosterone confirmed by blood work, I started taking topical lotion of testosterone
prepared by a compounding pharmacy. The
testosterone lotion delivers about 3 times that of Androgel high dose.[1] I noticed that DHEA improved my energy
similar to 12 ounces of green tea for one who avoids caffeine—has no
tolerance. The testosterone is subtle
since it absorption is slow and 98% is bound and thus not bioactive, just 2% is
circulating of the stored level. By the
6 month I noticed an elevation in mood—a lack of worry. Over the years—now
2020-- I have noticed that
I still have the muscle tone of an athlete, run every other day for a total 60
miles a month, and I can still delve into new areas of study with comprehension—none
in my age group do that. Some, like a
pianist, continue in the area of expertise. The GP who saw for 9 years has told
me that he will when older be taking testosterone, and my current physician at
the age of 60 has told me that is taking testosterone by injection.
For those
who want a
book on testosterone, Harvard Professor Abraham Morgentaler, M.D. an expert
with several journal articles is recommended.
His book, Testosterone for Life
(2009) is for a wide audience including
physicians. A far more complete list of
testosterone’s benefit is at http://healthfully.org/rc/id7.html.
The science
and trails
supported both steroids and with the articles posted on the website
healthfully.org, I came to understand why by 2005. I also know that the WHI
and HERS trials were
deliberate bad science. In 2003 I heard Prof.
Robert Langer of UCSD explain that Prempro is the worst formula of HRT, and the
results of the WHI don’t apply of other HRTs.
The older studies weren’t wrong, and they supported that estradiol and
testosterone would improve health and extend life. I pasted on my website dozens
of journal
articles on the 2 sex hormones by 2006.
My research in 2005 on DHEA had conflicting results, but knowing pharma
positon on steroid, I considered the article a confirmation of my 2002 my
tentative conclusion for DHEA, The early
examination of the progestogens[2] (not to be confused with
the synthetic progestins) was inconclusive for women past menopause as to the
question of it being taken along with estradiol. However, the 2019 revisit has
convinced me
because of autophagy that progesterone too would probably extend life. I am still frustrated over the lack of
research for it being a supplement for men.
Now, I know 15 years
later that the positive effects of the 4 hormones were mainly because of
autophagy and that they are neurosteroids.
The science in support of progesterone’s upregulating autophagy is
mostly after 2006. But does progesterone
add much to a combination of DHEA, estradiol, and testosterone? I don’t know, or how
progesterone functions in men. Science
still has a long way to go before it knows the place for the first time: the
hormonal role in autophagy, brain
functions, and CAWD is far from complete.
11.
Why menopause and
andropause: Approaching this
question of hormonal benefits from the direction of biological clock and the
role of hormones and that we have menopause and andropause,[3] I have come to believe
that it is part of the way that nature, shaped by village/tribal life, has
selected for to eliminate the burden of the less fit. I believe that the
downregulation with age
of autophagy and mitophagy occurs for group survival.[4]
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.[5]
There are several
puzzling issues, ones is why do mammals have menopause?[6] Why do males have andropause significantly
later than the female of their species?
The human answer of the advantage of elderly passing on knowledge does
work for other mammals, nor does the nurturing of related children for the
other mammals don’t have extended families.
It is for this reason that I believe the greatest advantage is hastened
eliminating of the less useful, the elderly.
Another puzzle is the change of age in western countries over the last
century, that though the average of is between 50 and 52, for India and the
Philippines it is 44.[7] Along with that has been in western diet
eaters earlier puberty and increased height.
To this I would speculate that it is because of hormone mimics, to which
I would place first soy beans.[8] A third is the lack of literature as to
menopause and andropause[9] among LSPs. We know that the AGES health conditions found
in the HSPs are virtually unknown in LSPs, would this also include the
subclinical hot flashes, moderate cognitive decline, mood swings, irritability,
forgetfulness, symptoms associated with menopause and for some andropause--none
of which have been noted for LSPs, that I know of. The world of science is full of interesting
puzzles.
I listed here at #5 the benefits for estradiol: lowering risks for conditions, Alzheimer’s
disease and other types of dementia, cancers, CVD, depression, diabetes,
obesity, osteoporosis rheumatoid arthritis, and on the upside are increased
sexual satisfaction, mood elevation, cognitive functions, firmer breasts,
healthier skin (less wrinkles). A
similar list is for testosterone. While
this Section, 3 has focused on MTDD,
RATP, DAP, and RAP, there are other factors
important factors, one of which is the role of the steroid sex hormones. “Induction
or inhibition of any of these pathways by environmental chemicals can result in
alteration of the natural balance of steroid hormones and could lead to
disruption of the endocrine system.” [10]
Something has caused changes to humans in the last hundred years that are
suggestive of environmental hormone mimic.
Puzzle on this, that puberty occurs over a year earlier and those of
English ancestry are over 2 inches taller than in the year 1900. The same is
occurring for other ethnic groups
in the United States and other countries on the western diet. There is evidence
that hormone mimics are the
principle cause, of which first I would put those in soy products. For more
on this see 4:4.
The same list
of
benefits can be made for testosterone, and again I refer you to my website
article summarizing its benefits at http://healthfully.org/rc/id7.html. and for estradiol /rc/id2.html. Those on the western diet benefit from
upregulating autophagy with sex steroid.
There are many contributors for this family of healing systems, and more
than just the 4 sex hormones, including DHEA, progesterone, and pregnenolone. Aspirin
that upregulate autophagy and journal
articles add others including calcium,[11] thyroid hormone,[12] and so on. There are decades of research to be done
before we have evidence as to types of health benefits, how they work as a
highly evolved team, and how to best delay natures methods of eliminating the
elderly.
12. DHEA and DHEAS introduction: The second sex hormone in the InCHIANTI study
was DHEA; why? The short answer is that
like with estradiol and testosterone, DHEA drop with age is driven by the eliminating
of the elderly from the community—see 9 above. “Evolution, through 500
million years, has progressively provided the peripheral tissues with the
enzymes able to make androgens and estrogens while high levels of DHEA, the
precursor of all sex steroids, have appeared much later with the primates
approximately 20 million years ago. “ [13]
The quote/article swallowing pharma’s bad estradiol theory, assumes that low
estradiol following menopause promotes elderly women survival. But eventually,
the level becomes too low for
“approximately 75% of postmenopausal women have too low circulating DHEA levels
and suffer from symptoms/signs of hormone deficiency.” (supra). A better
answer for the inclusion of DHEA in
the InCHIANTI Study is there is solid evidence for its health benefits, like
that of testosterone (and estradiol, not in the study). What is it?
I
hold that it is too low, because its role is much more than a precursor for
estradiol and testosterone. I also hold
that what is normal for a person in the 6th decade or older is too
low in estradiol and testosterone, when measured by the yardstick quality of
life, and the same applies to DHEA.
Further evidence for DHEA functions comes from the fact that it is
synthesized in the brain and adrenal cortex. Moreover the-20 million year as to
primate synthesis errs: Species as early
as the fish (and possible earlier ancestors).
Dehydroepiandrosterone has been
thought to have physiological
functions other than as an androgen precursor. The previous studies performed
have demonstrated a number of biological effects in rodents, such as amelioration
of disease in diabetic, chemical carcinogenesis, and obesity models. To date,
activation of the peroxisome proliferators activated receptor alpha, pregnane X
receptor, and estrogen receptor by DHEA and its metabolites have been
demonstrated. Several membrane-associated receptors have also been elucidated
leading to additional mechanisms by which DHEA may exert its biological
effects.[14]
Humans
and other primates are unique among animal species in that their adrenal glands
secrete large amounts of DHEA and DHEAS.[15]
Dehydroepiandrosterone sulfate (DHEAS) is the most
abundant circulating steroid hormone in humans and can readily be converted to
its parent steroid DHEA by tissue sulfatases.
The link between DHEA and aging has been raised by: (1) its well documented
age-related decline, and (2) a preventive effect of DHEA on numerous
age-related illnesses: ischemic heart-disease, cognitive impairment,
immunodeficiency, malignancies, osteoporosis. These effects have been
suggested by epidemiological studies in humans. Animal studies support a
protective effect of DHEA on these age-related diseases. The latest study
showed a beneficial effect
on well-being but these results need to be confirmed. . . . Animal studies support
a protective
effect of DHEA on these age-related diseases.
However, it remains
unknown whether these results in animals can be
transposed in humans, because adrenal secretion of DHEA seems to be particular
to primates. In humans, only a few studies have been performed. [16] Important pathways of steroid
catabolism to readily excreted metabolites are glucuronidation and sulfonation
of hydroxyl groups. Estradiol, testosterone, DHEA and hydroxylated metabolites
of these and other steroids readily form glucuronide and sulfate conjugates in
those fish species where these pathways have been examined. Little is known,
however, of the structure and function of the UDP-glucuronosyltransferase (UGT)
and sulfotransferase (SULT) enzymes involved in steroid conjugation in fish.[17]
What seems contradictory, isn’t
the claim
that primates only make DHEA was based upon location, the adrenal cortex. Fish
make DHEA entails another location. “The
observation was made that dehydroepiandrosterone (DHEA), as the unconjugated
steroid, and its sulfate ester (DHEAS) are present in the brain of adult male
rats (1). This finding was unforeseen because the
rodent steroidogenic glands, including the adrenals, do not secrete significant
amounts of DHEA (2). It led to the discovery of a
steroid biosynthetic machinery in the nervous system, in charge of producing
neurosteroids.[18] As a neurosteriod, and other functions, DHEA
plays an important health role.
“DHEA(S)
levels are high in
fetal life, decrease after birth, and show a marked pubertal increase to a
maximal level during young adulthood. In healthy adults, DHEAS levels decline
to 10–20% of peak levels by age 70 yr.” [19].
Serum levels
of DHEA and its sulfated conjugation product, DHEA sulfate (DHEAS), peak in men
and women in the third decade and decrease progressively and profoundly with
age”[20]
to very low quantities by the 7th decade. Bioavailability
50%, first pass converted by the liver to androsterone[21]
and etiocholanolone[22]. At 300 mgs orally the max serum level is
reached and little more from increasing over that amount.[23] It circulates mainly bound with albumin and
half that bond to SHBG. Most of the DHEA
is converted to DHEAS which isn’t significantly metabolized by the liver. DHEA
can significantly increase testosterone,
2 to 3 fold in women (a good thing). [24] Testosterone prevents sarcopenia, and having
good muscle tone is attractive and improves quality of life (for obvious
reasons). During pregnancy DHEA
contributes 9% of total estradiol (E2).[25] Testosterone, estradiol. and DHEA upregulate
autophagy. And all three are protective
of the mitochondria, which becomes significant for seniors. “In
the old rats following DHEA treatment, the state 3 respiration rates became comparable
to or increased beyond those of untreated young adults. In contrast to the old
rats. “ [26] DHEA increase
the production of ATP.[27]
Pharma’s because of sex-hormone phobia has their
KOLs
puts out the opposite information about conversion to testosterone, and that
DHEA doesn’t have health benefits.[28]
The health benefits and the use of DHEA would cause an increase in the usage
would create a positive hormone awareness with the increase usage also of HRTs,
thus DHEA usage is contrary to Pharma’s business model. Pharma because
couldn’t find in their
studies any major health hazards, so DHEA is treated like the antioxidants,
physicians “learn” that there are no benefit from the DHEA supplement.
Pharma would like to have it become a
prescription drug, like it is in Canada and other countries. This is why I have
over a 5 year supply of
DHEA, and the powder is inexpensive.
The articles concern DHEA is
conflicting. In 2005, I spent a week
tracking down the evidence, and couldn’t come to a firm conclusion, and that
was my second attempt. This was in my
more gullible period. Now I see the
shadow of bad pharma. The studies on
DHEA are often flawed: First given it
short half-life (50 minutes) for DHEA, its duration of for autophagy is too
short. It should be taken several times
a day. Second, the oral dose is too low
because of first pass metabolism by the liver.
Third, given that the liver doesn’t convert the DHEA to the sulfate on
first past from the intestines, the claim for longer active period based upon
conversion of DHEAS to DHEA is lacking support.[29] DHEAS has a
half-life of 11 hours, and 25 minutes for DHEA. DHEA conversion to testosterone
is over
estimated by 3 fold.[30] Even so, there is a significant body of
published research.
13. DHEA turns on autophagy: “Dehydroepiandrosterone
(DHEA) is an adrenal steroid of great recent
interest due to its anti-aging and anti-atherogenic effects; however, little is
known about its role in autophagy and endothelial senescence. . . . DHEA prevents
LA-induced endothelial
senescence by restoring autophagy
and autophagic flux through JNK activation.” [31] The benefit from autophagy is less when given
during the day because autophagy is turned on when insulin is low, which is mainly
at night, following intense or prolonged aerobic exercise, and when in the
fasting state; viz., when insulin is low. I take it sublingually when not eating
because
I like the way it makes me feel: a
moderate mental and physical pickup and suppression of appetite for an hour. Thus
often I take it in the morning during my
intermittent fast, which ends about 1 PM.
While the research is spotty, and
I have
yet to find a seminal article on DHEA, except one by a KOL (if it may be called
seminal). Given that and not wishing
to spend the months to write such a section in this book on CAWD, I will past
some points which support why InCHIANTI added to
testosterone and IGF-1 DHEA. The evidence
for brain functions has is in need of much more research.
14. DHEA neurosteroid:
DHEA is produced
de novo in the brain, and therefore is classified as neurosteroids. “This
term, neurosteroids, was proposed in 1981 (3). It
applies to the steroids, the accumulation of which occurs in the nervous system
independently, at least in part, of supply by the steroidogenic endocrine
glands and which can be synthesized de novo
in the nervous system from sterol precursors. The steroid precursors along
their biosynthetic pathways can be formed in situ
and assayed.” [32] “Some
neurosteroids have been shown to display neuroprotective properties, which may
have important implications for their potential use in the treatment of various
neuro-pathologies such as: age-dependent dementia, stroke, epilepsy, spinal
cord injury, Alzheimer’s disease (AD), Parkinson’s disease (PD) and
Niemann-Pick type-C disease (NP-C). This paper focuses on neuroprotection
afforded by neurosteroids.” [33] Estradiol,[34]
DHEA, and testosterone have also been shown to be effective in the treatment of
anxiety, depression, and other psychiatric conditions. “PREG [pregnenolone]
DHEA proved to provide
protection of dopaminergic (DA) neurons in the striatum of mice against MPTP. .
. . PREGS [pregnenolone] and DHEA, but not DHEAS, potentiate the effects of
N-methyl-D-aspartate (NMDA) in increasing intracellular calcium level. This
mechanism maybe responsible for growth of axons induced by DHEA. DHEAS
stimulates dendrites to grow, but underlying mechanism remains unknown [18,
24].” [35] And there are others in quite complex
interacting compounds of which some are neurosteroids, and others of interest
such as GABA gama amino-butyric acid and nicotinic acid.
Given it
high safety profile, low cost, drop in level in the 6th decade, its
many functions, and the positive results of supplementation, I started taking
it sublingually[36]
in 2002 I started taking DHEA, and have since 2017 double that amount to about
100 mgs daily—3 or 4 finger licks. A
micronized in oil form of 150 or 300 mgs has positive results,[37] but the bulk powder on Amazon is economical.
15. IGF-1 and
InCHIANTI Study: As
for the functions of IGF-1, nature has made the processes complex: there are
two IGFs (1 & 2) and six high
affinity IFG binding proteins (IGFBP-1 through 6). It is produced primarily
in the liver as an
endocrine hormone. Its production is
stimulated by the growth hormone HGH, and is in part regulated by a complex
system sensitive to nutritional status for which amino acids have the greatest
effect. Over 95% of UGF-1 is bound to
proteins. Both IGF-1 and IGF-2 have
structures--as their name implies--similar to insulin. IGF-2 is particular active
during
gestation.
There is no need to go into the
complex
processes, just to note that in the InCHIANTI study because of the selection of
testosterone, DHEA and IGF-1, it perked my curiosity. InCHANTI study noted that
the combination of
all 3 hormones at the highest level promoted the best long-term health by far
and the lowest 25% by far the worse. Two
ways to look at this, one is that the health promoting process of each of the
hormones works better when the others are at a normal level or above. Another
is that being low in all 3 is a
strongly associated marker for the pathologies associated with B-4: a strong
association with fructation, MTDD,
RATP, and diminished rate of autophagy.
This leaves us with the question of why is there an association. But
given the positive effects on MTD, and
autophagy,
Italy is a country for which the
medical
insurance system covers and tracks the use of HRT could possible confirm my speculation on the increased
benefit of combinations. Studies done, for example, of senior running
clubs didn’t look into their usage of hormones or their level of hormones. Life
extension is over 8 years, but the
hormonal role is not considered. As a long-term member of a health clubs (40
years), based on observations, I assume that there is the association: for it
would explain why some look younger than their age and do a more intense work
out with greater weights. From InCHANTI:
“According
to Roth et al,4 DHEA-S
has been considered one of the mediators [promoters]
of the relationship between caloric restriction and longevity in both animals
and humans. . . . Signaling of IGF-1 has been
considered a determinant of longevity, probably because of beneficial effects
on muscle, vasculature, and metabolism. However,
although IGF-1 was shown to be a predictor of cardiovascular
mortality in older men, the role of IGF-1 as a single determinant of longevity
is still debated. . . . On the basis of these contradictory data, it is unlikely that a
single anabolic hormone deficiency could be considered a reliable index of the
aging process. Interestingly, pluri-hormonal dysregulation rather
than single hormonal derangement has
been associated with the frailty syndrome, or the metabolic syndrome in older men. In men with
chronic heart failure, deficiency of more than 1 anabolic hormone identifies
patients with higher mortality rates.
. . . We found that independent
of age and multiple potential confounders, low circulating levels of multiple
anabolic hormones, including testosterone, IGF-1, and DHEA-S (in the lowest
quartiles of the population), were an independent predictor of mortality during
6 years of follow-up in older men. On the contrary, serum levels of each of
these hormones considered separately were not associated with significantly
differential mortality. In addition, we
were able to show that association between multiple hormone dysregulation and
mortality is not accounted for by potential confounders, such as cardiovascular
risk factors and cardiovascular morbidity.
. . . It is conceivable that
DHEA-S, testosterone, and IGF-1 have synergistic effects.”
The association above of the low 3 hormones lowering morbidity, that
it like applies also to CAWD. For those
in the lowest quartile for all three, there likely is extensive MTDD, RATP, and
RRA. The low androgen level is likely associated
with the major CC for CAWD covered in Section 4.
I am speculating
that IGF-1 has a positive effect
upon autophagy and is MTD protective like estradiol, testosterone, and
DHEA.
16. IGF-1 autophagy,
and a CC for MTDD: IGF-1 is a neurotrophic factor promoting
neuron growth and stimulates differentiation of progenitor cells to form
neurons. It promotes neurogenesis. “Insulin-like growth factor-1 (IGF-1) is an
important neurotrophic factor and its receptor IGF-1R is prevalently expressed
in the nervous system.” [38] Neurotrophic factors are biomolecules that
support the growth, survival or differentiation of both developing and mature
neuron, such as beta hydroxybutyrate a neurotrophin. Most of them belong to
1)-neurotrophin, 2) glial
cell-line derived neurotrophic factor family ligands, or 3) neuropoietic
cytokines. The list of these compounds is long and growing.
There is more evidence:
The effect
of serum withdrawal on the autophagy of dysfunctional mitochondria is prevented
by the addition of IGF‐1. As a result of the elimination of mitochondria with
deleterious mutations, excessive ROS production, characteristic of
dysfunctional mitochondria, is greatly reduced. Mitochondrial autophagy shares
a common mechanism with mitochondrial‐induced cell apoptosis, including
mitochondrial transition pore formation and increased ROS production.[39]
There is some evidence of such effect, but more research is
need.[40]
IGF-1 and its isoforms IGF-2 play a
significant role in autophagy affecting mTOR, p53, and other pathways
modulating autophagy.[41]
[42]
There are a number of articles
establishing the connection of IGF-1 and autophagy. Given the results of the
InCHANTI Study there
is a role of IGF-1 in health and survival, but would a supplement make a
difference has not been determined.
IGF-1 has other functions which promote health.
Its structure, as the name implies is similar
to insulin. Its production is stimulated
by hGH (human growth hormone. There are
6 IGF-1 binding proteins, which are in part regulated by insulin. There are
at least 2 isoform of IGF-1 which
are primarily produced by the liver as an endocrine hormone, and it has
important roles in childhood growth.
17.
Pregnenolone a major neurosteroid
Pregnenolone
18. Progesterone and
progesterins
From Wikipedia, (https://en.wikipedia.org/wiki/Progesterone) the labels
for each of the steroids has been lost in copying
It is synthesized from pregnenolone, and has a list
of functions
similar to that of the big 3 discussed, testosterone, estradiol, and DHEA. Along
with estrogen, progesterone has many of
the functions that regulate female reproductive organs. It is the major progestogen
(P4) of which
there are at least 8. Most of its
functions occur like with pregnenolone in the endoplasmic reticulum. Besides
it role in sexual development and
function, progesterone has many roles affecting the brain and nervous system
(neurosteroid), bone strength, skin elasticity, gall-bladder activity, insulin,
blood clotting, antioxidant properties, epidermal growth factor (EGF-1), and
inflammation. Its roles in autophagy
effects the uterus, brain, mammary gland, and promotes stimulation of apoptosis
in response to cancers of several tissue type including skin (melanoma), liver
uterus, breast. Given all these
functions and the well-established benefits of most formulations of HRT, this
makes a strong argument for its inclusion with estradiol in HRT, even for women
without a uterus. Note: I
have failed to find literature on its function for the male, and
therefore, I cannot comment on its inclusion with testosterone for hypogonadism. Given its metabolism to other
active
steroids, this undoubtedly accounts in part for many of progesterone’s many
functions.
19. Neurosteroid summary: Neurosteroids are synthesized from cholesterol, and are either
endogenous or exogenous steroids that rapidly alter neuronal activity. Of particular
interest are those made in the
brain or endocrine glands and that there are in the brain receptors for them.
“Some the steroids affect gene expression.; some are
classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate.
. . . Neurosteroids increase both synaptic and
tonic inhibition. They are endogenous regulators of seizure susceptibility,
anxiety, and stress” [43]
Given
the number of neurosteroids, their interactions, the use of
animal models, makes a detailed analysis of their activities and behavioral
effects a long way off. Nevertheless,
positive results have been observed among those with low levels through their
restoration to a youthful level for testosterone, DHEA, estradiol, and
pregnenolone, and others.
20. Testosterone, estradiol, and T2D: so what
is the evidence supporting a prophylactic role of the hormones in preventing the
spectrum of hyperglycemia, IR, and T2DM?
Given the role of fructation in CAWD, these steroids would in part act
to lower risks through lowering IR and T2DM.
Testosterone: The results of the NHANES Study won’t go
away in proper studies:
RESULTS—In
multivariable models adjusted for age,
race/ethnicity, and adiposity, men in the first tertile [lowest] of free testosterone
level were four times more likely to have
prevalent diabetes compared with men in the third tertile [highest] (odds
ratio 4.12 [95% CI 1.25–13.55]). Similarly, men in the first tertile of bioavailable
testosterone also were
approximately four times as likely to have prevalent diabetes compared with men
in the third tertile (3.93 [1.39–11.13]). . . . CONCLUSIONS—Low
free and bioavailable testosterone concentrations in the normal range were associated
with diabetes,
independent of adiposity. These data suggest that low androgen levels may be a
risk factor for diabetes in men.[44]
This
association in NHANES III is consistent with other population studies and
various mechanism that show mitochondrial and cyto-protection for sex steriods.[45]
NHANES is a frequently quoted study,
done in
phases beginning in 1971 through a program of the Center for Disease Control,
and continuing through to 2016, and possible currently.[46]
The results of the NHANES III support the role of testosterone in
lowering blood glucose and reducing MTDD.
Other studies had similar findings as to HRT and rate of T2DM. According to the MTTD root
cause theory I am presenting, and fitting in with TOFI, and lean people
developing T2DM, the association might be based on MTTD.
B. Estradiol:
In a controlled studied of postmenopausal women
it was shown that subsequent estradiol very significantly reduced the risk of
developing T2DM, and given its high rate among senior women, above 30% and its
very significant effect upon quality of life and longevity, this number along
would place estradiol first among healthful supplements (yes, supplements since
it is natural to the body.)
Type 2 diabetes developed
in 60 patients
during the follow-up period, which is the equivalent of 22 cases per 1,000
women-years. In the “hormones nonusers” group, diabetes developed in 10% (54 of
529 women; equivalent of 26.5 cases/1,000 women-years), whereas in the
“hormones users” group, diabetes developed in 4.16% (6 of 144 women; equivalent
of 12.1 cases/1,000 women-years). Transdermal 17-β-estradiol emerged as a
treatment that significantly reduced the risk of developing diabetes (RR 2.19,
95% CI 1.79–3.56; P = 0.006). Conclusion:
Our results
suggest a significant reduction in the incidence of type 2 diabetes in our
population of non-obese, healthy postmenopausal women who used transdermal
17-β-estradiol. This could suggest that, in some women, the estrogen deficiency
that occurs after menopause could represent a fundamental step in the process
of diabetogenesis.[47]
The
same has been found in the seminal article on natural HRT as to the benefits of
all the neurosteroids
Merely turning on a gene or starting a regulatory process calls
into action a wide variety of systems which adjust the process to maximize
benefits. The sex steroids are part of
complex systems of which they play major roles.
There are of 5 classes of steroids:
cholestanes (cholesterol), cholanes (cholic acid), pregnanes
progesterone), androstanes (testosterone), and estranes (estradiol). Among their
many actions there has been found
to be receptors in the MTD. In the 2007
article Actions of steroids in mitochondria:
Their
functions in the MTD brings me back to the question of why steroids levels drop
in the 6th decade and thereafter; its evolutionary advantage is the
elimination of the elderly burden. Their
functions in the MTD in part explains why HRT improves quality of life. The
youthful levels of the sex steroids
promote health, but in the 6th decade that function has been
compromised. Given the number of studies
which demonstrate their benefits, their action in the MTD, the lack of
prescribing HRT is a major CC for CAWD—end of case.
21.
An historical note
on hormones: Listen
and attend, there are important healthful observations. I had around 1963 came
to believe that senior men should take testosterone to improve quality of life
based upon my observation of my girlfriends grandfather, and her description of
his behavior. I believed he was going
through andropause, and it was difficult.
My mother then 53 had just gone through menopause. Both had a major reduction
in the quality of
life. This observation was consistent
with a recent Scientific American historical article on testosterone. My observations
of the elderly, the prevalent
general opinion, and a lack of negative articles affirmed my conclusion that
HRT for men and women would improve their quality of life. The article 1932
on testosterone and its
discover in Scientific American also covered its health benefits.
Having bought
a gym
membership in 1980 and used it almost daily, I had plenty of observations that
compared men and women on steroids to those not on them. Being into sports and
cycling, I didn’t think
I should go down their path, but by the age of 59 in 1962 I was feeling my age,
so I looked into the numerous androgens sold over the counter—legislative
restriction didn’t occur to about 2004.
The literature was pure marketing, but for DHEA. However, evil pharma
took a whack at it;
thus, there were 2 types of articles. I
didn’t back then know that pharma was the harpies attending the banquet of
health science. So following a long
tradition I bought DHEA powder in 2002.
Fearing changes in the law, the next year I bought a half pound. It was
restricted in Canada.
I took it
sublingually
to avoid liver degradation by the liver.
I was averaging under 20 mg daily, until about 2015, when I increased it
gradual until by 2018, I was taking sublingually 80 mg daily. I liked the way
it made me feel, a mild pick-me-up
like green tea for one who does take caffeine.
In 1998 I
read a book
of article on HRT for men and women and also on hGH, it confirmed my earlier
observation in 1963, In 2003, I sat
through a lecture by Robert Langer a professor of medicine at University of
California who partook in the Women’s Health Initiative (WHI) Study.[48] He
explained that the WHI studied only applied to Prempro. The same was
published. I sided with critics of the WHI and HERS such
as Prof. Langer, and concluded that estradiol and its structurally related
testosterone would improve health and extend life. I pasted on my website dozens
of journal
articles on the 2 sex hormones by 2006.
In 2003 I
had my
doctor check my testosterone level, and it was low. She told me that hypogonadism
is normal for a
man at 60. I felt like telling her “that
was bull shit, and I wanted take testosterone to improve my quality of life and
lower my risks associated with aging.”
Her attitude sucked. I felt like telling her, she was about my age, to
go to a gym and look for the seniors who were on testosterone, you could see
the difference!” I could she never went
to the gym.
In 2004, I
had a much
different doctor, one who cared about patients.
Knowing I had hypogonadism from
my last year’s blood work (I didn’t mention it), I asked Dr. Olifeson to check
my blood for testosterone. It came back
as I expected, and I started taking 10% testosterone 2 grams prepared from a
compounding pharmacy. The difference was
subtle. At 6 months I realized that I
hadn’t had a down though since starting HRT.
It confirmed a review by a doctor in which he switched from a Neurontin
for depression based on his reading about testosterone. My attitude on life
improved.
My research
in 2005
DHEA had conflicting results, but confirmed by 2002 conclusion tentatively, the
self-testing confirmed the neurosteroids effects. The examination of the progestogens[49] (not to be confused with
the synthetic progestins) was also inconclusive for women past menopause as to
the question of it being taken along with estradiol. However, the 2019 revisit
has convinced me
because of autophagy that progesterone too would probably extend life. I am still frustrated over the lack of
research for it being a supplement for men.
Now, I know 15 years
later that the positive effects of the 4 hormones were mainly because of
autophagy and that they are neurosteroids.
The science in support of progesterone’s upregulating autophagy is
mostly after 2006. But does progesterone
add much to a combination of DHEA, estradiol, and testosterone? I don’t know, or how
progesterone functions in men. Science
still has a long way to go before it knows the place for the first time: the
hormonal role in autophagy, brain
functions, and CAWD is far from complete.
[1]
According to Goodman and Gilman Pharmacology, only about 10% is absorbed from a
lotion. The lotion is 15% testosterone,
ac 2.5-gram dose. I first moisten my
upper torso, arms, and face before spreading the 2.5 grams of lotion.
[2] Kim,
Ha, Sook-Jeong Lee, et al Jan 2012, The neurosteroids,
allopregnanolone and progesterone, induce autophagy in cultured astrocytes
[3]
When women can no longer bear children and men father them.
[4]
There are other contributing factors including the increase rate of birth defects
with older parents,
[5] Vasconsuelo
Andrea, Lorena Milanesi, et al Sept 2013, Actions of 17β-estradiol and
testosterone in the mitochondria and their implications in aging
[6] “Reproductive cessation has also
been
documented in non-human primates, rodents, whales, dogs, rabbits, elephants and
domestic livestock.” Packer,
Craig, Marc Tala, et al, April
1998, Reproductive
cessation in female mammals
[7]
Wiki, menopause, 4/19
[8]
Daniel, Kaayla, 2007, The Whole Soy Story: the dark side of America’s favorite health
food, a seminal review of research.
[9]
Symptoms of andropause include erectile dysfunction, reduced libido,
irritability, loss of muscle mass, reduced physical activity, poor
concentration (focus), reduced cognitive functions. There is both a decline
in testosterone and
its bioactivity.
[10] James, Margret, Nov 2011, Steroid
catabolism in marine and freshwater fish
[11] Harr,
MW, CE Distehorst, Cold Spring Harbor, 2010, Apoptosis and autophagy decoding calcium
signals that mediate life or
death
[12] Lesmana, Rony, Rohit Sinha, et al, Jan 2016, Thyroid Hormone Stimulation
of Autophagy Is Essential for Mitochondrial
Biogenesis and Activity in Skeletal Muscle, “Thyroid hormone (TH) and
autophagy share similar functions in regulating skeletal muscle growth,
regeneration, and differentiation.”
[13] Labrie,
F, C. Larbie, Nov
2012, DHEA and intracrinology at
menopause, a positive choice for evolution of the human species
[14] Webb,
Stephanie, Thomas Geoghegan, et al, Oct 2008, The Biological
Actions of Dehydroepiandrosterone Involves Multiple Receptors
[15] Arnold,
Julia, Marc Blackman, Nov 2005, Does DHEA Exert Direct Effects on Androgen
and Estrogen Receptors, and Does It Promote or Prevent Prostate Cancer?
[16] Barrou, Zina, Philippee Charu, et
al, May 1997, Dehydroepiandrosterone
(DHEA) and aging
[17] James, Margret, Nov 2011, Steroid
catabolism in marine and freshwater fish
[18] Bauileu, Etienne-Emile, Paul Robel, April 1999 Dehydroepiandrosterone
(DHEA) and
dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. “These results clearly illustrate
a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free
interconversion of DHEA and DHEAS. DHEAS does not seem to represent a
circulating storage pool for DHEA regeneration, and therefore serum DHEAS is
unlikely to reflect bioavailable DHEA.”
[19]
Gordon, Catherine et al …..
[20] Arnold, Julia, Marc Blackman, Nov 2005, Does DHEA Exert Direct Effects on Androgen
and Estrogen Receptors, and Does It Promote or Prevent Prostate Cancer?
[23] An
increase of 3-fold in the infusion rate did not change any of these results,
indicating that enzyme availability was not a limiting step in the production
of estradiol (E2) from DHEA. . . .
The conversion ratio of DHEA into E2 increased during
pregnancy by 500-fold, and DHEA contributed 9% of maternal circulating E2.” Belisle,
Isaac Schiff, et al, Jan 1980, The Use
of Constant Infusion of Unlabeled Dehydroepiandrosterone for the Assessmentof
Its Metabolic Clearance Rate, Its Half-Life, and Its Conversion into Estrogens
[24]
Cupp, MJ, TS Tracy, Dec, 2002, Dietary Toxicology
and Clinical
Pharmacology, pp. 135
[25] Belisle Serge, Isaac Schiff, et al, Jan 1980 Unlabeled Dehydroepiandrosterone
for the Assessment of Its Metabolic
Clearance Rate, Its Half-Life, and Its Conversion into Estrogens
[26] Patel, Minal, Surenda Matyare,
July 2006, Treatment
with dehydroepiandrosterone
(DHEA) stimulates oxidative energy metabolism in the cerebral mitochondria:
A comparative study of effects in old and young adult rats
[27] Patel, Minal, Surenda
Matyare, Jan 2007, of dehydroepiandrosterone (DHEA) treatment on
oxidative energy metabolism in rat liver and brain mitochondria, a
dose-response study
[28]
Without health benefits and cause of harm, then why “has it remained banned as
a supplement in Canada, the United Kingdom, Australia, and New Zealand”? Wiki,
prasterone, April 2019 (Prasterone is
DHEA, one of its 14 names listed in the Wiki article)
[29] Hammer,
Fabian, Sandra Subtil, et al, June 2005 No
Evidence for Hepatic Conversion of Dehydroepiandrosterone (DHEA) Sulfate to
DHEA: In Vivo and
in Vitro Studies
[30] Belisle Serge, Isaac Schiff, et al, Jan 1980, Unlabeled Dehydroepiandrosterone
for the Assessment of Its Metabolic
Clearance Rate, Its Half-Life, and Its Conversion into Estrogens
[31] Lee, Min, KIim Eun, et al, Sept 2015, Dehydroepiandrosterone prevents
linoleic
acid-induced endothelial cell senescence by increasing autophagy
[32] Bauileu, Etienne-Emile, Paul Robel, April 1999 Dehydroepiandrosterone
(DHEA) and
dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids
[33]
Wojtal, Katarzyna, Michal Trojnar, et al, 2006, Endogenous neuroprotective factors:
neurosteroids
[34] Douma,
SL, C Husband, et al, Oct 2004, Estrogen-related
mood disorders: reproductive life cycle
factors “Clinical recovery
from depression postpartum, perimenopause, and post-menopause through
restoration of stable/optimal levels of estrogen has been noted.”
[36]
The oral dose is only about 5% bioavailable because of first pass metabolism by
the liver. Secondly it is a mild
stimulant comparable to a coup of green tea.
Third, it suppress appetite about an hour. Fourth I like the feeling
it creates in my mouth.
[37] Buster, john Peter
Casson, et al, April 1992,
Postmenopausal steroid replacement with micronized dehydroepiandrosterone:
Preliminary oral bioavailability and dose proportionality studies
[38] Zhou, Yan-Ling, Liu Shu-Qing et al, Dec 2016, The
expression of insulin-like growth factor=1 in senior patient with diabetes and
dementia
[39]
Gu, Yiping, Chunjie Wong, et al, October 2004, Effect of IGF‐1 on the balance between autophagy of
dysfunctional mitochondria and apoptosis
[40] Evalo, Maria, Isabel Ruiz-Palmero, et al , Aug 2012, Molecular mechanisms
involved in the regulation of neuritogenesis by estradiol: Recent advances
[41] Gu, Yiping, Chunjie Wang, et al, Oct 2004, Effect of IGF‐1 on
the balance between autophagy of dysfunctional
mitochondria and apoptosis. “The
effect of serum withdrawal on mitochondrial autophagy is prevented by the
addition of IGF‐1.”
[42] Feng, Zhaohui, Arnold Levine, July 2010, The regulation of energy metabolism
and the
IGF-1/mTOR pathways by the p53 protein. mTOR
and p53 are autophagic regulatory
hormones.
[43]
Ruddy Doodipala, 2010, Chapt 8 Neurosteroids: endogenous role in the human brain and
therapeutic potential in Progress in
Brain Research, pg. 113
[44] Selvin, Elizabeth, Feinleib Manning, et al, Feb 2007 Androgens and Diabetes
in Men: results from the Third National Health and
Nutrition Examination Survey (NHANES III)
[45] Gavrilova-Jordan,
Larisa, Thomas Price, 2007, Actions of
steroids in mitochondria
[46]
It is part of the National Health and Nutrition Examination Survey, and is at https://www.cdc.gov/nchs/nhanes/index.htm Findings have been frequently referenced
as
established figures of the US population such as for NAFLD.
[47] Rossio, Rosario, Giorgia Origiliani et al, Mar 2004 Transdermal 17-β-Estradiol
and Risk of
Developing Type 2 Diabetes in a Population of Healthy, Non-obese Postmenopausal
Women
[48] Langer, Robert, Emily White, et al 2003, The Women’s
Health
Initiative Observational Study: Baseline characteristics of Participants and
Reliability of Baseline Measures. It is just a review of
the data collected in the observational study.
No mention was made of Prempro or medroxyprogesterone, which was the
focus of his lecture to about 800 mostly med students and professors at UCSD
auditorium.
[49] Kim,
Ha, Sook-Jeong Lee, et al Jan 2012, The neurosteroids,
allopregnanolone and progesterone, induce autophagy in cultured astrocytes
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