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6:2 HORMONAL HEALTH

LIKE THE OTHER CHAPTERS THE ILLUSTRATIONS DON'T PASTE NOW.  EDITING IS INCOMPLETE

SECTION 6—2-Sex and related hormones, fine tunes autophagy  6/9/19

 

 

https://upload.wikimedia.org/wikipedia/commons/thumb/1/13/Steroidogenesis.svg/450px-Steroidogenesis.svg.png

  1. Steroid hormonal connections to CAWD:  a good story their history that illustrates another sad chapter in the history of “modern medicine”.   Again I must thank Marcia Angell for her eye-opening book on how pharma functions (see appendix).   Sex hormones in the broader family are a vital part of an optimally operating autophagy system.  Of particular interest are the sex steroid testosterone, dihydrotestosterone, estradiol, and several other steroids”:  pregnenolone,[1] DHEA, and progesterone along with the growth factor IGF-1 The chart of above gives you some idea of the number of bioactive steroids complexity. 

    Steroid hormones are cholesterol derivatives that serve as signaling molecules to coordinate the expression of complex gene programs in higher eukaryotes. These molecules exert their effects by diffusing into cells and interacting with specific intracellular receptors. Receptors for each of the major classes of sex and adrenal steroids have been characterized (9, 2, 36). In the absence of their cognate ligands, the steroid hormone receptors remain sequestered in the cytoplasm through interactions with large multiprotein complexes containing heat shock proteins. However, the binding of ligand causes the steroid hormone receptors to be released from these complexes and translocated into the nucleus (Pratt 1993). Once inside the nucleus, the activated receptors regulate the expression of target genes by binding as homodimers to short DNA sequence motifs, termed hormone response elements (HREs) (Glass 1994). In this manner, the steroid hormone receptors function as ligand-activated transcription factors.  . . . In addition to receptors with established ligands, approximately 30 other members of the nuclear hormone receptor family have been isolated from vertebrates. [2]

    They are synthesized in the gonads, adrenal cortex, and some other tissues including for most in the brain by glial cells.[3]  Their functions and benefits are essentially for an understanding of their importance, but often not stressed in the literature.[4]  Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester may improve cognitive and memory function. In addition, they may have protective effects against schizophrenia.  There are many other health benefits independent of autophagy, such as neurosteroids, androgen effects, lipo regulators, mitochondrial functions, etc. There is much to gain from understanding their importance of these steroids.  Given the many functions of the steroids made from cholesterol, the war on cholesterol and these steroids is another example of pharma profiting from illness.  I shall let the evidence do the talking.  Nature doesn’t evolve such a large number of steroids to harm mammals. 

Many pieces affect autophagy, for example the role of insulin, mTOR, and AMKP (more are in regulatory chart at 3:5, 7).   Though I am not into a survey of affecters; none the less, I am focusing on sex hormones because the “science’ printed in the medical text books and press are supplied by pharma through their KOL system.  Yes, again we have a case of pharma promoting illness and again I am responding to the harm done.  Again we have pharma tell us that something which is healthful causes illness.  Again we have pharma “proving” that nature’s systems making us sick, in this case with the sex hormones.[5]  And again there is a mountain of journal articles proving the opposite.  This chapter both exposes their crapolla and also supports topics in this Section the fixes.  Natural hormones are healthful; and low levels are pathogenic, more than merely a marker, because NHRT lowers risk, while lowing blood pressure has minimal effects in the real-world population. 

    Autophagy functions to keep our cells in peak performance, and when that is not possible to dismantle them and thereby have them replaced with healthier ones.  It should be remembered that apoptosis is a form of autophagy that apoptosis in a properly functioning system occurs to cells whose condition merits orderly dismantling, and when in sufficiently good condition the repair wing of autophagy is turned on.  Senescence has the advantage of turning down the functions of a cell which is leaking reactive chemical or could be if not turned down; however, if they accumulate due to RATP such as with the elderly and infirmed the functions of the tissue are compromised.  Thus down regulation of these healing process contributes significantly to CAWD.  Androgens promote autophagy.

The performance of autophagy is not easy to measure.  Unlike other process, because autophagy is a complex collection of process, there is no simple measurement such as pulse is for myocardial contractions or research measurement such as the dimensional average for MTDD.  Autophagy involves many structures (3:5 2) and processes whose regulation is mostly not directly dependent upon other autophagic processes; viz., one can be turned up, while the another process isn’t.  The complexity of process, the various involved structures, their microscopic dimension, the variety of process together entail a gap in observations.  And this gap widens in connecting, for example, the nexus between lysosome performance and illness for humans.  Moreover, using the rat as a model is thin, in part because of the limited, late interest in autophagy.[6]   And there is the technology barrier of the process occur in minuscule subunits of cells:  not easy to measure.  However, the biology behind autophagy strongly support connections to CAWD.  Autophagy is another piece in the CAWD puzzle that fits.  Merely considering what has proceeded on the first three of the B-4, and the amount of energy used for cellular repair and order dismantling entails that the long-term significantly diminished rate of autophagy is expletive of CAWD.  Much of what follows in this Section’s subsequent chapters rides upon diminished autophagy (such as sensitivity to uric acid, diminished rate of replacement of collagen, and in prior (3:3 and 3;4) IR, t2d, and excessively large lipid droplets in the liver and other tissues).  

What is the degree of evidence, for example, that it is a long-term underperformance of autophagy that is causing the neurodegenerative diseases—or at least a major CC?   Three topics needing more research are, autophagy, LSPs the basics of their bio-functional al differences, and B-4 role in CAWD.  I feel like Darwin with a very incomplete fossil record, but with enough fossil to show in some cases such as with Equus (horses) that there was an orderly progression of changes leading to the modern horse.

For simplicity, I will avoid the complexity of 17 related sex hormones (diagram above) and their many functions since the science is weak and a discussion contributes little to the focus of this book.  The research is thin because sex hormones are natural, they can’t be patented and they are healthful.[7]  There is much more to the sex steroids then the development of sexual characteristics.[8]  These other functions are the reason that nearly every cell has special receptors for them, estrogens, testosterone, dihydrotestosterone, pregnenolone, and DHEA that I know of—and nature doesn’t expend the ATP to promote illness (though pharma does).[9]  For these reasons it seems that the principle sex hormones estradiol, DHEA, testosterone (and probably others such as pregnenolone and progesterone would promote autophagy, and thus health; do they?[10]  I am focusing on the above 3, since there is strong evidence for their health benefits, and of course, pharma being pharma has sullied the evidence base.[11]  I had for 15 years settled for association of the health benefits of the 3 hormones[12] now I found the why.  I went from prevention happened in the black box, to a rough diagram of the workings of the black box.  So what are some of the health benefits and why?

 

2.   Sex hormonal benefits:  The evidence in support of restoring hormones to a youthful level is solid; the evidence for unnatural analogues is mixed (#6 for estrogen with a progestin and pharma’s hatchet job with the aid of NIH’s trials).   A large body of study support hormone replacement therapy (HRT, estradiol and a progestin for women and testosterone for men).  Because the sex hormones are neurosteroids, promote autophagy, and partially regulate a n  umber 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/imporoves 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 this is only what I have uncovered in journals).  All these claims are supported by journal articles, which are to be found at http://healthfully.org/rc/id7.htm.  A similar longer list for estrogen and a progestin:[13] 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. 

                        

UTI, Osteoarthritis  NFALD, and venus thrombosis for E2, look them up for TTT

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 though estradiol though not an androgen, it has a very significant androgen effect through conversion into testosterone.  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.[14]  Without it, there won’t be an increase in muscle mass, thus another way pharma does studies that show no 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 them less brittle (#7).  The importance of resistance training, of the need for progesterone for health bone are often overlooked, 

Both men and women have widely distributed receptors for these hormones, and nature functions to promote health when it contributes to survival of the community.  Research shows that these hormones are a CC for autophagy, there are receptors in the inner membrane of MTD, and they are neurosteroids.  It is not surprising that the taking of steroids extends life.  Those with the lowest levels have a very significant increase in mortality.  This was found in the InCHIANTI study below, and a number of others studies listed in healthfully.org, see supra links.   



[1] “Pregnenolone and its 3β-sulfate, pregnenolone sulfate, like DHEA, DHEA sulfate, and progesterone, belong to the group of neurosteroids that are found in high concentrations in certain areas of the brain, and are synthesized there.”  Wiki pregnenolone June 2019. 

[2] Kliewer, Steven, John Moore, et al, Jan 1998, An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway

[3] Glia, also called glial cells or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system. They maintain homeostasis, form myelin, and provide support and protection for neurons.[1] In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells, and microglia, and in the peripheral nervous system glial cells include Schwann cells and satellite cells. They have four main functions: (1) to surround neurons and hold them in place; (2) to supply nutrients and oxygen to neurons; (3) to insulate one neuron from another; (4) to destroy pathogens and remove dead neurons. They also play a role in neurotransmission and synaptic connections,[2] and in physiological processes like breathing.[3][4][5] While glia were thought to outnumber neurons by a ratio of 10:1, a recent study provides evidence for a ratio of less than 1:1.[6]  . . . Glial cells make up about half the total volume of the brain and spinal cord. The glia to neuron-ratio in the cerebral cortex is 3.72 (60.84 billion glia (72%); 16.34 billion neurons), Wiki, Glial, June 2019.

[4] Fifteen years (2019) after reading hundreds of journal articles—mainly in search of their benefits—did I come across their production in the brain and function as neurosteroids.  If mentioned, it wasn’t stressed.  I have long before 2004 considered the modus operandi essential, what separates a pill pusher from medical scientist.   

[5] By showing the evidence is contrary what the NIH and KOLs spout, I am again confirming the dismal assessments of Relman and Angell in the introduction section.  This confirms Goldacre assessment: “They frame the topic.” 

[6] Though first observed in the 1960s when orderly cell destruction was first observed, early research was thin.  “Difficulties in studying the phenomenon meant that little was known until, in a series of brilliant experiments in the early 1990’s, Yoshinori Ohsumi used baker’s yeast to identify genes essential for autophagy.”  The Nobel Prize in Physiology or Medicine 2016, Press release, Oct 2016 to Yoshinori Ohsumi.  Interest picked up between 2000 and 2013, as measured by journal articles; however, nearly all of them are on genes, processes, structures, and very few on associated pathologies, and those published are mainly on cancer, inflammation,  and neurodegenerative conditions.  .

[7] A patent can be obtained if mixed with a patented drug which is why a progestin is added to estradiol.  The FDA has given out patent now on the lowest of standard, such as adding an over-the-counter drug such as acetaminophen, a slow release formula, ancient drugs such as colchicine, and now what our body makes such as allopregnanolone whose branded name is Zulresso, and has for a course of treatment for postpartum depress a cost in the US of $34,000.  Wiki allopregnanolone, April 2019.  

[8] Many of the sex steroids are neurosteroids and some act as positive allosteric modulators of GABA receptors.

[9] It is why hormone mimics such made by soy beans, and some of the progestins are bad for health, they occupy those receptors and block some or all of the positive effects of the natural sex hormones. 

[10] Very probably the other such as Pregnenolone, and other progestogens have some role in affecting autophagy.  

[11] I had failed to find, after several hours of searching, an article clearly showing an increased risk of uterine cancer for unopposed natural estrogen.  A similar sham has been worked with testosterone and prostate cancer.  The Harvard Professor Abraham Morgentaler, has done the research and published it both in a journal article, and in his book Testosterone for Life.  See his chapter 7, pages 115 to 139.  He found in research using the archives of the Harvard University Medical Library, the 1941 article by Drs. Huggins & Hodges that started the myth; their finding was based on a single patient who had been castrated.  The 1981 study done at the Memorial Sloan-Kettering Cancer Center over the course of 18 years on 52 men with terminal prostate cancer, that all but for had been castrated or given estrogen (the same hormonal effect).  The increase in cancer growth rate occurred with the re-introduction of testosterone by injection.  (the results for the 4 not castrated were not given in the article.)  Morgentaler calls the increased growth a flare phenomenon.  Millions of men have been castrated for profits, and I believe many more women, because not only with uterine cancer is the ovaries removed but also with the hysterectomy.  The myth of cancer growth has a horrific price. This happened to my 2nd mother-in-law, who was also put on valium.  The quality of her remaining 36 was poor.  They included depressions, mental institutions, electroshock treatment, drugs, and cancer 3-times over 20 some years. 

[11] As usual I must cherry pick the evidence based upon my understanding of how cells function, pharma functions, and evolution.

[12] The fourth would be progesterone; however, in my review of the journal articles the evidence is supporting its healthful functions were less, and thus I couldn’t include it in the list.  Besides the 3 contribute to an increased level of progesterone, if needed.  I have not after several hours been able to find out the role of progesterone in males.

[13] 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. For more on these hormones see links in next paragraphs.    ] 

[14] 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.  InCHIANTI Longevity study:  Relying on the InCHIANTI Study of men followed 6 years, the cohort with the lowest 1/4th of all 3, testosterone, DHEAS, and IGF-1 (insulin like growth factor 1—there are 2) had a death rate of 2.44 higher than the 3/4th above them.[1] 

Several lines of evidence suggest that the aging process is associated with a decline in anabolic hormones and increase in catabolic hormones.22 In this study, we evaluated the 3 key anabolic hormones: bioavailable testosterone, DHEA-S, and IGF-1. Each of these anabolic hormones has a direct impact on lipid and glucose metabolism.23-25  evidence has indicated that low testosterone, IGF-1, and DHEA-S levels are good predictors of cardiovascular disease and diabetes in men.5,10,26 Furthermore, we have previously shown that a low testosterone level is inversely related with inflammatory markers and predicts the development of anemia in the older population.27,28 Both cardiovascular disease and anemia are 2 independent predictors of mortality in older men.29  … Compared with men with levels of all hormones above the lowest quartile, men with 1, 2, or 3 hormones in the lowest quartile had an HR for mortality of 1.47 (95% CI, 0.88-2.44), 1.85 (95% CI, 1.04-3.30), and 2.29 (95% CI, 1.12-4.68) (test for trend, P = .006), respectively (Table 2). After adjusting for confounders, including age, BMI, educational level, smoking, alcohol and caloric intake, physical activity, log (IL-6) levels, and chronic disease such as diabetes, hypertension, peripheral artery diseases, coronary heart disease, congestive heart failure, stroke, Parkinson disease, COPD, asthma, and cancer, the HRs for mortality were 1.04 (95% CI, 0.56-1.95), 1.34 (95% CI, 0.67-2.65), and 2.44 (95% CI, 1.09-5.46), respectively (test for trend, P <.001) (Table 3).  [to have all 3 in the lowest 25% entail after adjusting for existing confounding variable a 2.44 death risk above the first 3 groups.  In other words, the healthies of the low hormones still died at a much higher rate than the healthiest of the 75% group].  . . . The mortality rates (events per 100 person-years) were 2.9 in group 0, 6.2 in group 1, 16.7 in group 2, and 46.0 in group 3 (P = .007, test for trend).[2]

This raises the question as to how the 2 sex hormones and IGF-1 can be associated with health, and thus life extension.  The connection of testosterone[3]  and estradiol with autophagy comes in many directions, and there are other healthful effects for the sex hormones.  Given the difference of only one functional group and a ring structure, explains why both through autophagy have the same benefits.[4] [5]   DHEA and IGF-1 will be discussed at the end of this subsection.   Note:  based on my extensive review of the literature I am assuming that estradiol, if women were included in InCHIANTI study, would have resulted in similar positive result.  Including estradiol, is there evidence that the 4 hormone are fine-tuning the autophagy processes? 

 

    TESTOSTERONE                              ESTRADIOL                DEHYDROEPIANDROSTERONE         

The chemical structure of testosterone.The chemical structure of estradiol.  Dehydroepiandrosteron.svg

4.  TESTOSTERONE much more than an anabolic steroid:  But as an anabolic steroid it 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 androstane 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. However, I don’t share the optimism of the author as to drug intervention.  Evolution has finely tuned the functions of neurosteroids and the steroidal hormones.  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).[14]

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.[15] [16]  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,[17] 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[18] 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.   

 

5.   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. “ [19] [20]  It has been shown to following a cerebral ischemic event to inhibit apoptosis by increasing autophagic cellular repair.[21]  “It is also protective of mammary epithelial cells (MEC) by a tightly controlled balance be reparative autophagy and apoptosis.” [22]  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.[23]  Our study reveals a unique mechanism through which ERβ/PTEN signaling induces cell death in TCAM2 by autophagy and necroptosis[24]

 

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.” [25] 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.[26]  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).[27]

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: [28] 

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). [29] 

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).[30]  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.[31]  

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. 

 

6.  HERS, WHI, horse estrogen (E2):  “1992, Premarin became the number one prescribed drug in the U.S.”[32]  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.[33]  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.[34]  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.[35]   

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.” [36]  

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.[37]

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.[38]  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.  Very few physicians will recommend HRT unless 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.  For very possible the best 5-page account of why doctors are pill pushers, and it is sympathetic to their situation 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).[39]  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[40] that turns up autophagy and lowers the risk for cancer.  The major Harvard’s Nurses’ Study[41] 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, thus many of the same benefits.  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.[42]  The current Wikipedia article for the WHI study makes no mention of equine estrogen or that medroxyprogesterone blocks some of the benefits of estrogen.[43]  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.[44]  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.[45]  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.[46] 

 

 

https://upload.wikimedia.org/wikipedia/commons/thumb/8/89/Biphosphonate_Structural_Formulae.png/200px-Biphosphonate_Structural_Formulae.png

General structure of bisphosphonate



[1] Maggio, Marcello, Fulvio Lauretani, Et al, Nov 2007, Relationship between low levels of anabolic hormones and 6-year mortality in older men:  the aging in the Chianti Area (InCHIANTI) Study.  Again we have the case of a hatchet job by pharma on the benefits of DHEA.  (The sulfate is the storage form of DHEA.)  The best way to take it to avoid the liver catabolism of DHEA is sublingually.  Supplements with the sulfate group I haven’t been able to find.  The reason might be as dark as that with low dose aspirin, enteric coated aspirin, taking a statin in the day when the body makes cholesterol at night, and so on. 

[2] Maggio, Marcello, Fulvio Lauretani, Et al, Nov 2007, Relationship between low levels of anabolic hormones and 6-year mortality in older men:  the aging in the Chianti Area (InCHIANTI) Study

[3] Gao, Fengyi, Guoping, Li, et al, April 2018, Autophagy regulates testosterone synthesis by facilitating cholesterol uptake in Leydig cellsł This article shows the role of autophagy upon testosterone levels. 

[4] While some would consider the difference in CVD a counter example, this is another case of association leading to the wrong conclusion.  For LSP both sexes are at extremely low risk.  As of now, I am not aware of the cause for this difference in HSPs.

[5] Vasconsuelo, Andrea, Lucia Pronsato, et al, Nov 2011, Role of 17β-estradiol and testosterone in apoptosis

[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] Baulieu, E, Nov 1998, Neurosteroids: a novel function of the brain

[14] Torro-Urrego, Luis Garcia-Segura, et al, June 2016, Testosterone Protects Mitochondrial Function and Regulates Neuroglobin Expression in Astrocytic Cells Exposed to Glucose Deprivation

[15] 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

[16] 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

[17] 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.  

[18] Articles on male hormones at http://healthfully.org/malehormones/ , and the concise review with links of the evidence at http://healthfully.org/rc/id7.html

[19] Luine, Victoria, Sept 2014, Estradiol and cognitive function: Past, present and future

[20] Yi Jing, Xue Tang, June 1995, Functional implication of autophagy in steroid-secreting cells of the rat

[21] Li, L., S. Sun, et al, June 2017, Effects of Estradiol on Autophagy and Nrf-2/ARE Signals after Cerebral Ischemia

[22] 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.  

[23] Deng, L J Feng, et al., April 2010, The novel estrogen-induced gene EIG121 regulates autophagy and promotes cell survival under stress

[24] 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

[25] Li, L., S. Sun, et al, June 2017, Effects of Estradiol on Autophagy and Nrf-2/ARE Signals after Cerebral Ischemia

[26] Holli, K, J Isola, et al, Sept 1998, Low biologic aggressiveness in breast cancer in women using hormone replacement therapy

[27] Schierbeck, Louise, Lars Rejnmark, et al, October 2012, BMJ, Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

[28] Studd, John, March 2010, Ten reasons to be happy about hormone replacement therapy: a guide for patients

[29] Di Saia, Philip, Wendy Brewster, et al, Dec 2000, Breast cancer survival and hormone replacement therapy: a cohort analysis

[30] The same logic probably applies to testosterone and prostate cancer.  See discussion of testosterone below.

[31] 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).

[32] Vance, Dwight, 2007, Premarin: The intriguing history of a controversial drug

[33] At http://healthfully.org/fhr/ there are dozens of such articles; at http://healthfully.org/fhr/id19.html  the summation article.

[34] Gambacciani, Marco, Guiseppe Rosano, et al, Aug 2002 Clinical relevance of the HERS trial 

[35] 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. 

[36] Dennis Walkins, October 2003, Scientific American, Hormone Hysteria? 

[37]    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.

[38] Keating, Nancy, Paul Cleary, et al, April 1999, Use of hormone replacement therapy by postmenopausal women in the United States

[39] 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.

[40] 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

[41] Holmes, Michelle, Wendy Chen et al (4 women0 March 2010, Aspirin intake and survival after breast cancer

[42] Wiki hormone replacement therapy April 2019, and

[43] 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.

[44] 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.    

[45] “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.   

[46] 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.   

7.  Osteoporosis and estrogen (and arthritis and the other hormones);  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, and the 2001 numbers for fractures have nearly double over the last 20 years.  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.” [1]  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” [2]  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”[3]Male patients affected by rheumatoid arthritis[4] have been shown to possess low serum testosterone” [5] and a  similar finding for osteoarthritis.  Compared to women, the decline in men is gradual.[6]   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 too must extend to DHEA, since it too lowers the risk for osteoporosis.[7] [8] Progesterone also is effective in preventing osteoporosis.  Progesterone also has been proven very effective at preventing osteoporosis and reversing it.[9]  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?). [10] 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.[11] 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.[12]

          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.[13]  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.” [14]  “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.” [15]  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.[16]   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.[17]  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.” [18]

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.[19]  

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.[20]  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.[21]    

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, and if it was mentioned in their chapter on sex steroids, I didn’t retain the information.  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.” [22]  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).” [23]

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.[24]    

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).[25] 

 

8.  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,[26] 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. 

      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.”[28]  “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)”.[29]  Free and serum testosterone levels were significantly lower in the RA males than in either the AS [ankylosing spondylitis] group or the healthy controls”[30]  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.   

 

9. 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 considering buy over-the-counter androgens.  After a review of the literature in 2001, I bought 2 different steroids, 4-androstene-3,17-diol and DHEA—they were still being sold over-the-counter.  The 4-androstene was to bitter to take sublingually; however, DHEA had a mild amine test, similar to testosterone.  Suspecting government regulation by 2003 I had stocked piled 125 grams of DHEA powder from Bulk Nutrition.  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.[31]  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.  By at 6 months, I noticed an elevation in mood—a lack of worry.  Over the years I have noticed that I still have the muscle tone of an athlete, and in 2019 I was 76, and I can still delve into new areas of study with comprehension.  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 confirmed by 2002 my tentative conclusion,  The early examination of the progestogens[32] (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.

 

10. 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,[33] 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.[34]     

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.[35]

There are several puzzling issues, ones is why do mammals have menopause?[36]  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.[37]  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.[38]  A third is the lack of literature as to menopause and andropause[39] 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.” [40] 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,[41] thyroid hormone,[42] 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.   

 

11.  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. [43] 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).  

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 when the yardstick is 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.[44]

Humans and other primates are unique among animal species in that their adrenal glands secrete large amounts of DHEA and DHEAS.[45] 

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 sup 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. [46]  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.[47]

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.[48]  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.” [49]  DHEA is produced by the adrenal cortex and is the most abundant steroid in humans. 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”[50] to very low quantities by the 7th decade.  Bioavailability 50%, first pass converted by the liver to androsterone[51] and etiocholanolone[52].  At 300 mgs orally the max serum level is reached and little more from increasing over that amount.[53]  It circulates mainly bound with albumin and half that bond to SHBG.  Most of the DHEA is converted to DHEA-S which isn’t significantly metabolized by the liver.  DHEA can significantly increase testosterone, 2 to 3 fold in women (a good thing). [54]  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).[55]  Testosterone and DHEA upregulate autophagy.  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.[56] 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.[57]  DHEA has a  half-life of 11 hours, and 25 minutes for DHEA.  DHEA conversion to testosterone is over estimated by 3 fold.[58]   Even so, there is a significant body of published research. 

 

12.  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.” [59]  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.  

File:Enzyme Model.jpg

Allosteric regulation of an enzyme

13.  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.” [60]  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.” [61]  Estradiol,[62] 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].”[63]  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 in 2003 and have in the last 2 years double that amount to about 100 mgs daily.  A micronized in oil form of 150 or 300 mgs has positive results.[64]

14. 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.  It was noted that the combination of all 3 hormones in 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.  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.  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.   

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 androgens with morbidity, that it is like also applies to CAWD.  For those in the lowest quartile for all three, there likely is extensive MTDD, RATP, and RRA.  The low androgen is likely one of many results of a cellular system stressed, with a wide assortment of measurable consequences, of several of the significant ones have been developed in Section 4.      

 

15.  IGF-1 CC for MTDD and Autophagy Though I couldn’t find evidence that that IGF-1 is synthesized in the brain, and thus a neurosteroid, this does not entail that it doesn’t affect brain functions and might function synergistically with neurosteroids.  There is some evidence of such effect, but more research is need.[65] IGF-1 and its isoforms play a significant role in autophagy affecting mTOR, p53, and other pathways modulating autophagy.[66] [67] 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.  I suspect that like with the sex hormones degree of benefits is determined by degree of infirmity. 

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.  It is primarily produced by the liver as an endocrine hormone, and it has important roles in childhood growth.   

Laron syndrome, for which there is significant interest in that this rare condition which causes dwarfism also confers resistance to the pathogenic consequences of a high sugar diet, and other health benefits associated with a paleo diet such as a low rate of cancer and CVD.  Laron is characterized by a lack of GH receptors, that patients do not respond to injections of hGH.  The opposite of this is acromegaly for which there is an over production of pituitary GH, which produces gigantism.  The science on the IGF family of hormones is thin. 

 

Pregnenolone.svg
Pregnenolone

16. Pregnenolone a major neurosteroid is an endogenous steroid, precursor to other steroids and a metabolite of some steroid.  “It is the main steroid synthesized from cholesterol in mammals and invertebrates.  It has three mains sources of synthesis, the gonads, adrenal glands and brain.” [68]  It is an intermediate in the biosynthesis of most of the steroid hormones. Its importance is indicated because it is manufactured in the MTD.[69] It is a neurosteroid and has additional other bioactivities.  “Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization.” [70]  It is an over-the-counter medication. Like DHEA, and like DHEA has a sulfate conjugate. In both forms like DHEA it is found in high concentrations in the brain; both are neuroprotective.   Pregnenolone binds to the CB­­1 cannabinol receptor and to microtubule-associated protein-2 (MAP2).[71] It prevents CB1 receptor agonists such as tetrahydroxcannabinol from fully activating that receptor.[72]   As a neurosteroid pregnenolone controls formation of and stabilization of mircotubules in neurons and have other neural developmental properties as well as a negative allosteric modulator of GABAA.  Pregnenolone crosses the blood-brain barrier while the sulfate form can’t. Pregnenolone decreases in the elderly[73]  Pregnenolone is relevant as endogenous biomarker of brain-related disorders.  Pregnenolone might have therapeutic potential for these pathologies. Pregnenolone treatment induces beneficial effects and it is well tolerated.” [74]  Currently most of the research on pregnenolone is in the area of marijuana effects including addiction. Pregnenolone improves memory, stimulates neurotic growth, modulates pituitary-adrenal axis, increase GABA receptors, positive modulates NMDA receptors, elevates other neurosteroids such as allopregnanolone, increases neurogenesis, and is protective against an assortment of mental illness[75]

Like most of the major steroid, the oral route leads to first pass metabolism of 95%, which is why I take pregnenolone and DHEA sublingually, and testosterone as a skin lotion from a compounding pharmacy.  All 3 are neurosteroid, and I am in my late 70s. 

As for being used as a supplement when either in poor health or in the 6th decade or older, there are obstacles: 

“Pregnenolone has low bioavailability and is subject to high metabolism.[4] Oral administration of 50 or 100 mg pregnenolone has been found to have minimal or negligible effect on urinary levels of testosterone and testosterone metabolites, including of androsterone, etiocholanolone, 5β-androstanediol, androstadienol, and androstenol (and/or their conjugates), and this suggests that only a small amount of pregnenolone is converted into testosterone.[12][13]  [KOL spun wrong, this shows that very little of oral pregnenolone survives transport to the liver, thus there is very little that could be converted to testosterone.]  This is in accordance with findings on the conversion of DHEA into testosterone, in which only 1.5% of an oral dose of DHEA was found to be converted into testosterone.[12] [76] [The same obstacle for pregnenolone applies to DHEA.]  

Based on the above the first pass liver obstacle entails sublingual administration.  I have attempted to find a bulk source, like can be done with DHEA, so that it may be taken sublingually, and have failed on Amazon at a price comparable to DHEA.  The powder is $93/10 grams through Bulk Supplements.  An internet search June of 2019 did not find another supplier for small amounts.[77]  The capsule product is but 8% pregnenolone and the remainder of the powder is filler.  Judging from the number of sellers on Amazon, there must be a significant market to this supplement, to which its bioavailability entails another naturalistic product that lacks significant health benefits.

          This brings me full circle, in that there are benefits to hormonal replacement for the infirmed and elderly.  However, relying on the marketplace is a minefield.  Given the complexity of bio-systems, the large number of steroid hormones, I would proceed with caution.  Some things do work, for which seeing is the proof:  look at the muscle bound weight lifters in the gyms.  Investigating what they take is beyond my scope of research.  However, based on observations I would give a star to HGH, testosterone, and dihydrotestosterone.  Estradiol is added to this list for women since about 10% is converted to the androgen testosterone, which is sufficient to prevent for the elderly women muscle loss.  DHEA[78] increase the level of free testosterone by competing for SHBG and albumin, thus entailing that some of its benefits are based on testosterone and estradiol.  Evidence also supports benefits of DHEA for health.  Progesterone clearly is beneficial for women, but for men I could find dispositive evidence.  Another possible for the list is Androstane, for which I couldn’t find a source or extensive literature.  Again we have the problem of complexity and a system of research that is market oriented.  There are 31 related compounds to androstene:  “5α-Androstane is reported to be effective as an androgen, in spite of having no oxygen substitutions.[1][2][79] 

I have spent over the last 20 years several thousands of hours trying to answer question about benefits and related topics for the steroids, and have come to many an end road.  If I went down every tunnel, I would never see the daylight.  Just remember that the elderly should be on steroids because evolution operates to eliminate the elderly: these sex steroids promote health, mental functions, and improves the quality of life.   

 

 Progesterone metabolism

From Wikipedia, (https://en.wikipedia.org/wiki/Progesterone) the labels for each of the steroids has been lost in copying

17.  Progesterone and progesterins 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. 

 

18.  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. Or 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” [80]  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.   

 

19.  Testosterone, estradiol, DHEA IGF-1, and T2DM:  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:    

Apply to each SS (sex steroid):  Expand from internet word doc.  Obesity & Diabetes:  the drop of estradiol increases LPL which regulates weight, distribution of fat, and activity.  Gary Taubes, Good Calories, Bad Calories, 398, Taubes Why we Get Fat, 90-91, and Wade at,  In the obese, estrone is 40% higher at. Weight related issues (metabolic syndrome, insulin resistance, & diabetes) are associated with drop in estradiol, at.  Likely mechanism is a reduction in the related hormone DHEA whose metabolite (7-oxo-DHEA) promotes significant weight loss (at) and is neuroprotective (at).  Note, JK takes DHEA 40 mg sublingually; it diminished appetite for one hour.  

 

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 (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.[81]

This association in NHANES III is consistent with other population studies and various mechanism that show mitochondrial and cyto-protection for sex steriods.[82] 

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.[83]  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.[84]

The same has been found in the seminal article on natural HRT as to the benefits of all the neurosteroids

DHEA:



IGF1:

Expand from internet word doc.  Obesity & Diabetes:  the drop of estradiol increases LPL which regulates weight, distribution of fat, and activity.  Gary Taubes, Good Calories, Bad Calories, 398, Taubes Why we Get Fat, 90-91, and Wade at,  In the obese, estrone is 40% higher at. Weight related issues (metabolic syndrome, insulin resistance, & diabetes) are associated with drop in estradiol, at.  Likely mechanism is a reduction in the related hormone DHEA whose metabolite (7-oxo-DHEA) promotes significant weight loss (at) and is neuroprotective (at).  Note, JK takes DHEA 40 mg sublingually; it diminished appetite for one hour.  

Chemical-diagram flow chart

 

B-4, sex steroids:  At the heart of the processes leading to IR and t2d is the B-4, which starts with their function to reduce the risk for MTDD.  As by now you have realized that the mammalian body is a very complex system with many, many bioactive chemicals making fine adjustments, many of them found with origins in early eukaryotes and preserved in fungus, plants, insects and other phylums and orders. 

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:   

ABSTRACT:  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. [85]

Their functions in the MTD brings me back to the question of why steroids levels drop in the 6th decade and thereafter and its evolutionary advantage of eliminating the elderly.  Their functions in the MTD in part explains why supplementation improve quality of life.  The normal levels of the sex steroids in the MTD is tuned to 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 is big part of the explanation as to why they are salubrious.  End of case. 

End fine



[1] Francis, RM, Dec 2001, The effects of testosterone on osteoporosis in men  (a seminal review article)

 [2] Wiki, Osteoporosis, April, 2019. 

[3] Tuck, S, R Francis, 2009, in Advances in the Management of Testosterone Deficiency Vol. 37, pp. 123-133    Testosterone, Bone and Osteoporosis

[4] 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

[5] 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

[6] 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. 

[7] 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.”

[8] Gordon, Catherine, Julie Glowacki, Aug 1999, DHEA and the skeleton (through the ages)

[9] Lee, JR, Aug 1991 Is natural progesterone the missing link in osteoporosis prevention and treatment?

[10]  The NEJM article on bias

[11] 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

[12] 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

[13] 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.

[14] Russell, RG, July 2011, Bisphosphonate:  the first 40 years

[15] Russell, RG, MJ Rogers, July 1999. Bisphosphonates: from the laboratory to the clinic and back again

[17] From WorstPills.org, Dec. 2008 and pasted at http://healthfully.org/dnd/id13.html

[18] Supra

[19] AFFP (American Academy of Family Physicians) endorses ACP Guidelines on treating Osteoporosis, May 11, 2017 article, at aafp.org. 

[20] 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. 

[21] 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.”

[22] Lee, JR, Aug 1991, Is natural progesterone the missing link in osteoporosis prevention and treatment? 

[23] Prior, JC, May 1990, in Oxford Academic, Endocrine Reviews Progesterone as a Bone-Trophic Hormone

[24] 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, it wasn’t the doctor’s fault but that of tobacco ethics shaping treatments. 

[25] 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. 

[26] Insightful would be hormonal measurements of the elderly of the LSPs.

[27] Wiki osteoporosis May 2019.

[28] Wiki, arthritis, May 2019

[29] 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,

[30] 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

[31] 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. 

[32] Kim, Ha, Sook-Jeong Lee, et al Jan 2012, The neurosteroids, allopregnanolone and progesterone, induce autophagy in cultured astrocytes

[33] When women can no longer bear children and men father them. 

[34] There are other contributing factors including the increase rate of birth defects with older parents, 

[35] Vasconsuelo Andrea, Lorena Milanesi, et al Sept 2013, Actions of 17β-estradiol and testosterone in the mitochondria and their implications in aging

[36]  “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

[37] Wiki, menopause, 4/19

[38] Daniel, Kaayla, 2007, The Whole Soy Story:  the dark side of America’s favorite health food, a seminal review of research. 

[39] 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.

[40] James, Margret, Nov 2011, Steroid catabolism in marine and freshwater fish

[41] Harr, MW, CE Distehorst, Cold Spring Harbor, 2010, Apoptosis and autophagy decoding calcium signals that mediate life or death

[42] 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.”

[43] Labrie, F, C. Larbie, Nov 2012, DHEA and intracrinology at menopause, a positive choice for evolution of the human species

[44] Webb, Stephanie, Thomas Geoghegan, et al, Oct 2008, The Biological Actions of Dehydroepiandrosterone Involves Multiple Receptors

[45] Arnold, Julia, Marc Blackman, Nov 2005, Does DHEA Exert Direct Effects on Androgen and Estrogen Receptors, and Does It Promote or Prevent Prostate Cancer?

[46] Barrou, Zina, Philippee Charu, et al, May 1997, Dehydroepiandrosterone (DHEA) and aging

[47] James, Margret, Nov 2011, Steroid catabolism in marine and freshwater fish

[48] 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.”

[49] Gordon, Catherine et al …..

[50] Arnold, Julia, Marc Blackman, Nov 2005, Does DHEA Exert Direct Effects on Androgen and Estrogen Receptors, and Does It Promote or Prevent Prostate Cancer?

[51] Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone.  It is a weak androgen with a potency that is approximately 1/7 that of testosterone [which is sufficient for women to avoid sacroponia], and also to dihydrotestosterone  and androstenedione, Wiki April 2019

[52] Etiocholanolone, also known as 5β-androsterone, as well as 3α-hydroxy-5β-androstan-17-one or etiocholan-3α-ol-17-one, is an etiocholane (5β-androstane) steroid as well as an endogenous 17-ketosteroid that is produced from the metabolism of testosterone.  It stimulates the immune system. Wiki etiocholanolone, April 2019. 

[53] 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

[54] Cupp, MJ, TS Tracy, Dec, 2002, Dietary Toxicology and Clinical Pharmacology, pp. 135

[55] 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

[56] 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)

[57] 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

[58] 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

[59] Lee, Min, KIim Eun, et al, Sept 2015, Dehydroepiandrosterone prevents linoleic acid-induced endothelial cell senescence by increasing autophagy

[60] Bauileu, Etienne-Emile, Paul Robel, April 1999 Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids

[61] Wojtal, Katarzyna, Michal Trojnar, et al, 2006, Endogenous neuroprotective factors:  neurosteroids

[62] 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.”

[63] Supra 336

[64] Buster, john Peter Casson, et al, April 1992, Postmenopausal steroid replacement with micronized dehydroepiandrosterone: Preliminary oral bioavailability and dose proportionality studies

[65] Evalo, Maria, Isabel Ruiz-Palmero, et al , Aug 2012, Molecular mechanisms involved in the regulation of neuritogenesis by estradiol: Recent advances

[66] 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.”

[67] 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. 

[68] Vallee, Monique, June 2016, Neurosteroids and potential therapeutics:  focus on pregnenolone

[69]  Ray Griffiths, Mitochondria in Health and Disease, P 119

[70] Wiki, pregnenolone, July 2019

[71] Pertwee, Roger, Endocannabinoids and Their Pharmacological Actions

[72] Vallee, Monique, Sergio Vitiello, et al, Jan 2014, Pregnenolone Can Protect the Brain from Cannabis Intoxication

[73] Vermeulen, A., J. P. Deslypere, et al, Jan 1988, Adrenocortical function in old age: response to acute adrenocorticotropin stimulation

[74] Vallee, Monique, June 2016, Neurosteroids and potential therapeutics:  focus on pregnenolone

[75] Marx, CE, DW Bradford, et al, sept 2011, Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence, in a special issue of Neuroscience on neurosteroids. P 78-90.

[76] Wiki, pregnenolone, May 2019

[77] Prescribe for Life offers kilogram portions, starting at 1 kg for $478, a fraction of BulkSupplements, for which 60 grams would cost $500; this comes to 33 times the cost per gram. 

[78] The storage form of DHEA, DHEAS, I have not been able to find available through retail outlets, though it should be.  Like with pregnenolone, DHEA is marketed in pill form, when it should be taken sublingually.   

[79] Wiki, androstane, May 2019.  The article is just 3 sentences. 

[80] Ruddy Doodipala, 2010, Chapt 8  Neurosteroids:  endogenous role in the human brain and therapeutic potential in Progress in Brain Research, pg. 113

[81] 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)

[82] Gavrilova-Jordan, Larisa, Thomas Price, 2007, Actions of steroids in mitochondria

[83] 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. 

[84] 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

[85] Gavrilova-Jordan, Larisa, Thomas Price, 2007, Actions of steroids in mitochondria

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On how daily excessive fructose damages the mitochondria and thus is the main cause for the conditions associated with the Western diet--much, much, more than insulin resistance, type-2 diabetes, and weight gain