Book on fructose, mitochondria, and the sickest of mammals

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 7^th 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 GABA­_A 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. 

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 2^nd 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 3^rd 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.

• Steroid-induced osteoporosis (SIOP) arises due to use of glucocorticoids – analogous to Cushing's syndrome and involving mainly the axial skeleton. The synthetic glucocorticoid prescription drug prednisone is a main candidate after prolonged intake. Some professional guidelines recommend prophylaxis in patients who take the equivalent of more than 30 mg hydrocortisone (7.5 mg of prednisolone), especially when this is in excess of three months.^[65] Alternate day use may not prevent this complication.^[66]
• Barbiturates, phenytoin and some other enzyme-inducing antiepileptics – these probably accelerate the metabolism of vitamin D.^[67]
• L-Thyroxine over-replacement may contribute to osteoporosis, in a similar fashion as thyrotoxicosis does.^[55] This can be relevant in subclinical hypothyroidism.
• Several drugs induce hypogonadism, for example aromatase inhibitors used in breast cancer, methotrexate and other antimetabolite drugs, depot progesterone and gonadotropin-releasing hormone agonists.
• Anticoagulants – long-term use of heparin is associated with a decrease in bone density,^[68] and warfarin (and related coumarins) have been linked with an increased risk in osteoporotic fracture in long-term use.^[69]
• Proton pump inhibitors – these drugs inhibit the production of stomach acid; this is thought to interfere with calcium absorption.^[70] Chronic phosphate binding may also occur with aluminium-containing antacids.^[55]
• Thiazolidinediones (used for diabetes) – rosiglitazone and possibly pioglitazone, inhibitors of PPARγ, have been linked with an increased risk of osteoporosis and fracture.^[71]
• Chronic lithium therapy has been associated with osteoporosis.^{[55] [45]}

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.   

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 6^th 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 7^th 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 6^th 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 6^th 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 6^th 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.