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6:2 HORMONAL HEALTH

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



Chapter 2, Sex hormones and others hormones fine tune autophagy:  1. Sex hormone connection     2. InCHIANTI longevity study   3.  Sex hormones benefits   4. Estradiol and testosterone protect MTD   5. Testosterone, and neurosteroid    6. Estradiol HRT is healthful    7. HERS, WHI, horse estrogen and MPA    8. Osteoporosis and estrogen    9. Epidemic of osteoporosis and osteoarthritis    10. My historical note on hormones    11. Why menopause and andropause?   12. DHEA and DHEAS introduction   13. DHEA turns on autophagy   14. DHEA neurosteroid   15. IGF-1 and InCHIANTI Study   16. IGF-1 autophagy, and CC for MTDD   17. Pregnenolone a major neurosteroid   18. Progesterone and progesterin   19. Neurosteroid summary   20. Testosterone, estradiol   21. An historical note on hormones


 


  1. Steroid hormonal connections to CAWD:  a good story their history; it illustrates another sad chapter in the history of “modern medicine”.   Again, I must thank Marcia Angell for her eye-opening book on how pharma functions (see appendix).  I was still under the delusion of Keynsian economics with managed capitalism in the area of health care.   To put it another way if pharma can set up as standard care lowering cholesterol and avoiding saturated fats, and gain government support for the lipid hypothesis, then they can change the way we do medicine for to maximize profits.  So, what is the evidence for steroid and where is the carpolla? 

    There are receptors in every cell for them including the mitochondria, and a number of tissues can manufacture them.  Nature functions to survival to promote survival and thus passing of the genes, but also to cully the burden of the elderly from the village.  Reducing sex steroids functions in the mitochondria as to its functions through a reduction in their synthesis promotes less ATP and thus a weakening of the immune system with its infectious consequence.  Sex hormones in the broader family are a vital part of an optimally operating autophagy system.  Of particular interest are the sex steroid testosterone, dihydrotestosterone, estradiol, DHEA, and progesterone and their structurally related steroids.  Strong evidence is for testosterone, estradiol,  Both steroids trigger a complex molecular mechanism that involves crosstalk between the mitochondria, nucleus, and plasma membrane, and the cytoskeleton plays a key role in these interactions. The result of this signaling is mitochondrial protection.” [1] of these I have reviewed in depth the literature on the sex hormones, pregnenolone,[2] DHEA, and progesterone along with the growth factor IGF-1 and IGF-2. The chart of above gives you some idea of the number of sex hormones, and thus the Herculean task of sorting out their functions and interactions. 

    Steroid hormones are cholesterol derivatives that serve as signaling molecules to coordinate the expression of complex gene programs in higher eukaryotes. These molecules exert their effects by diffusing into cells and interacting with specific intracellular receptors. Receptors for each of the major classes of sex and adrenal steroids have been characterized. In the absence of their cognate ligands, the steroid hormone receptors remain sequestered in the cytoplasm through interactions with large multiprotein complexes containing heat shock proteins. However, the binding of ligand causes the steroid hormone receptors to be released from these complexes and translocated into the nucleus. Once inside the nucleus, the activated receptors regulate the expression of target genes by binding as homodimers to short DNA sequence motifs, termed hormone response elements (HREs). In this manner, the steroid hormone receptors function as ligand-activated transcription factors.  . . . In addition to receptors with established ligands, approximately 30 other members of the nuclear hormone receptor family have been isolated from vertebrates. [3]

    They are synthesized in the gonads, adrenal cortex, and some other tissues including in the brain by the glial cells.[4]  Because pharma frames the topic, their function as neurosteroids has been buried.[5]  Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester may improve cognitive and memory function. In addition, they may have protective effects against schizophrenia.” [6]  There are many other health benefits independent of autophagy, such as neurosteroids, androgen effects, lipo regulators, mitochondrial functions, etc. There is much to gain from understanding their importance of these steroids.  Given the many functions of the steroids made from cholesterol, the war on cholesterol and these steroids is another example of pharma profiting from illness.  I shall let the evidence do the talking.  Nature doesn’t evolve such a large number of steroids to harm mammals. 


Yes, again we have a case of pharma promoting illness and again I am responding to the harm done.  Again we have pharma tell us that something which is healthful causes illness and framing the topic for their ends.  Again we have pharma “proving” that nature’s systems making us sick, in this case with the sex hormones.[7]  And again there is a mountain of journal articles proving the opposite.  This chapter both exposes their crapolla and also supports theme in this Section of the healthful fixes.  Natural hormones are very healthful; and low levels are associated with age related conditions and morbidity both in LSPs and HSPs.  They are more than merely a marker, because natural hormones play key homeostasis functions and autophagy.   


For simplicity, I will avoid the complexity of 17 related sex hormones (diagram above) and their many functions since the science is weak and a discussion contributes little to the focus of this book.  The research is thin because sex hormones are natural, they can’t be patented, and they are healthful.[8]  There is much more to the sex steroids then the development of sexual characteristics.[9]  These other functions are the reason that nearly every cell has special receptors for them, estrogens, testosterone, dihydrotestosterone, pregnenolone, and DHEA—and nature expends the ATP to promote wellness.  Pharma makes hormone mimics for sake of patents and to promote illness.  It is why Prempro in the U.S. is most popular HRT and the worse (#7).[10]   


I am focusing on estradiol, DHEA, and testosterone, since there is strong evidence for their health benefits.  The cancer association is the work of bad pharma.[11]  I had for 15 years settled for association of the health benefits of these 3 hormones[12] now I found the why.  I went from prevention happened in the black box, to a rough diagram of the workings of the black box.  If they are so good they should extend life. 


 


2.  InCHIANTI Longevity study:  Relying on the InCHIANTI Study of men followed 6 years, the cohort with the lowest 1/4th of all 3, testosterone, DHEAS, and IGF-1 (insulin like growth factor 1—there are 2) had a death rate of 2.44 higher than the 3/4th above them.[13] 


Several lines of evidence suggest that the aging process is associated with a decline in anabolic hormones and increase in catabolic hormones.22 In this study, we evaluated the 3 key anabolic hormones: bioavailable testosterone, DHEA-S, and IGF-1. Each of these anabolic hormones has a direct impact on lipid and glucose metabolism.23-25  evidence has indicated that low testosterone, IGF-1, and DHEA-S levels are good predictors of cardiovascular disease and diabetes in men.5,10,26 Furthermore, we have previously shown that a low testosterone level is inversely related with inflammatory markers and predicts the development of anemia in the older population.27,28 Both cardiovascular disease and anemia are 2 independent predictors of mortality in older men.29  … Compared with men with levels of all hormones above the lowest quartile, men with 1, 2, or 3 hormones in the lowest quartile had an HR for mortality of 1.47 (95% CI, 0.88-2.44), 1.85 (95% CI, 1.04-3.30), and 2.29 (95% CI, 1.12-4.68) (test for trend, P = .006), respectively (Table 2). After adjusting for confounders, including age, BMI, educational level, smoking, alcohol and caloric intake, physical activity, log (IL-6) levels, and chronic disease such as diabetes, hypertension, peripheral artery diseases, coronary heart disease, congestive heart failure, stroke, Parkinson disease, COPD, asthma, and cancer, the HRs for mortality were 1.04 (95% CI, 0.56-1.95), 1.34 (95% CI, 0.67-2.65), and 2.44 (95% CI, 1.09-5.46), respectively (test for trend, P <.001) (Table 3).  [to have all 3 in the lowest 25% entail after adjusting for existing confounding variable a 2.44 death risk above the first 3 groups.  In other words, the healthies of the low hormones still died at a much higher rate than the healthiest of the 75% group].  . . . The mortality rates (events per 100 person-years) were 2.9 in group 0, 6.2 in group 1, 16.7 in group 2, and 46.0 in group 3 (P = .007, test for trend).[14]


This raises the question as to how the 2 sex hormones and IGF-1 can be associated with health, and thus life extension.  The connection of testosterone[15]  and estradiol with autophagy comes in many directions, and there are other healthful effects for the sex hormones.  Given the difference of only one functional group and a ring structure, explains why both through autophagy have the same benefits.[16] [17]   DHEA and IGF-1 will be discussed at the end of this subsection.   Note:  based on my extensive review of the literature I am assuming that estradiol, if women were included in InCHIANTI study, would have resulted in similar positive result.  Including estradiol.  So what are the benefits and why? 




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

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

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

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

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

[6] Wiki, neurosteroids, Sept 2019

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

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

[9] Many of the sex steroids are neurosteroids and some act as positive allosteric modulators of GABA receptors.  The functions upon the mitochondria in the brain entails superior mitochondria functions, until andropause and menopause.

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

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

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

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

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

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

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

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

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




3.       Sex hormone benefits: 


    TESTOSTERONE                              ESTRADIOL                DEHYDROEPIANDROSTERONE         


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


          The evidence in support of restoring hormones to a youthful level is solid; the evidence for unnatural analogues is mixed (#6 is on pharma’s hatchet job with the NIH using Prempro, horse estrogen and medroxyprogesterone in the WHI study, the most-costly of their studies).  A large body of studies support hormone replacement therapy (HRT, estradiol and a progestin for women and for men testosterone).  Because the sex hormones are neurosteroids, promote autophagy, and partially regulate a number of bodily functions there is a diverse long list of benefits, which are supported by journal articles (see links thereto below on my website).  Testosterone reduces mitochondrial dysfunction, insulin resistance, fat mass, depressed mood, inflammation, vascular aging; increases/improves muscle strength, erythropoiesis, collagen in skin, sexual interest and cognitive and brain functions in general including mental health (it is a neurosteroids); reduces risk for dementia, T2DM, osteoporosis and bone fractures, rheumatoid arthritis, cardiovascular disease, atherosclerosis, reduces rate of morbidity and there are more benefits.  All these claims are supported by journal articles, which are to be found for testosterone at http://healthfully.org/rc/id7.htm  and a similar list for estrogen and a progestin:[1] with evidence in addition for these reduces risk macular degeneration and increased health through positive effect upon collagen in the skin and breasts.  With 38% of women having taken HRT by the 1990s (no figures for men) pharma took notice and the NIH did two large trials using the worst of the HRTs; the results had the desired effects upon belief and usage of HRT among women.  For a review of the benefits with links go to my published articles on HRT for men (http://healthfully.org/rc/id7.html) and for women (http://healthfully.org/rc/id2.html) article and my collection of journal article for men (http://healthfully.org/malehormones/) and for women (http://healthfully.org/fhr/).  


       Four often missed facts:  First, that estradiol though not an androgen, it has a very significant androgen effect through conversion into testosterone—about 10%.  Second is the muscle loss of aged women can be prevented with a significant daily dose of estradiol, testosterone, or DHEA.  Sarcopenia (frailty from lack of muscle) has a major impact upon health and quality of life. Third is that muscles are a demand system, thus muscle gain from HRT requires significant resistant training.[2]  Without weight training, there won’t be an increase in muscle mass, thus another way for pharma to “prove” that there aren’t physical benefit for HRT.  Fourth point missed is that estradiol slows the loss of calcium in bone, and this slows remodeling, while progesterone increases remodeling, thus the two operate as a system for rejuvenation of the bones; thereby making bones less brittle (#7).  As a demand system, bone benefit from impact training such as running and jumping rope, as too the cartilage.  Runners have less joint problems.  Point 2, 3, and 4 also apply to men.    


 


4.  Testosterone and estradiol protect the mitochondria:    Consistent with MTDD causing CAWD, that hormones that promote mitochondrial functions would lower risks for CAWD.  The evidence including the modus operandi has been demonstrated for estradiol and testosterone:  “Our results indicate that testosterone improves cell survival and mitochondrial membrane potential and reduces nuclear fragmentation and reactive oxygen species (ROS) generation.” [3] Estradiol and testosterone enter the MTD and improve functions therein: 


A decline in the mitochondrial functions and aging are two closely related processes. The presence of estrogen and androgen receptors and hormone-responsive elements in the mitochondria represents the starting point for the investigation of the effects of 17β-estradiol and testosterone on the mitochondrial functions and their relationships with aging. Both steroids trigger a complex molecular mechanism that involves crosstalk between the mitochondria, nucleus, and plasma membrane, and the cytoskeleton plays a key role in these interactions.  The result of this signaling is mitochondrial protection. Therefore, the molecular components of the pathways activated by the sexual steroids could represent targets for anti-aging therapies. In this review, we discuss previous studies that describe the estrogen- and testosterone-dependent actions on the mitochondrial processes implicated in aging.[4]


I was surprised to find in the strip-down mitochondria receptors for steroids; there value must be major benefits to justify the production of these receptors. 


Steroid receptor-dependent interactions with mitochondria may include transcriptional regulation of nuclear DNA-encoded mitochondrial proteins, transcriptional regulation of mitochondrial DNA-encoded proteins, or indirect effects on mitochondria due to interactions with cytoplasmic signaling peptides and non-genomic control of cation fluxes. These interactions may play a role in mitochondrial-dependent processes of oxidation. . ..  STEROID RECEPTORS IN THE MITOCHONDRIA:  The prevailing view of the nucleus as the site of steroid receptor action, while mitochondrial action is regulated by secondary messengers, has been challenged in the last decade. Several studies demonstrate the existence of steroid receptors in mitochondria. . .. Similar evidence [to glucocorticoids] exists for localization of estrogen receptor (ER) α and ERβ to the mitochondria. . .. These relatively nonspecific results led to more conclusive evidence that the estrogen binding was mediated by a true receptor using specific antibodies. . ..  In previous work from our laboratory, we have cloned and expressed a novel PR [progesterone], termed PR-M, from human adipose and aortic cDNA libraries.[57]. , . .  STEROID AND MITOCHONDRIAL INTERACTION; There are several mechanisms whereby steroid hormones may affect mitochondrial function. These include transcriptional control of mitochondrial proteins encoded by nDNA, transcriptional control of nuclear-encoded transcription factors affecting nDNA-encoded mitochondrial proteins, transcriptional control of mitochondrial proteins encoded by mtDNA, activation of cytosolic signaling peptides by plasma membrane or cytosolic steroid receptors that subsequently affect the mitochondria, and possible non-genomic effects by a mitochondrial membrane-bound receptor. . ..  Estrogen may indirectly affect mitochondria by activation of MAPK.  . . . Non-genomic actions of estradiol in the mitochondria have also been demonstrated. Estradiol and other agonists caused an immediate increase in mitochondrial Ca2+ in HeLa cells via the mitochondrial Ca2+ UP. [5]


That which is good for the MTD, must also be good for the ATP hungry brain.


 


5.  Testosterone and neurosteroids:  As an anabolic steroid testosterone improves the quality of life and functions of elderly men and women who will experience significant muscle loss.  Falls are by the 7th decade a significant contributor to mortality.   In addition, like estradiol, the addition of testosterone prevents additional bone loss through positive bone remodeling (#7), and also like DHEA and estradiol it is a neurosteroid,[6] and like them is also synthesized in the brain and other peripheral tissue (more on this below).  In the brain it has psychological functions and reduces the risk for psychiatric conditions and dementia.  Testosterone is a steroid (derived from cholesterol) in the androstanes class that binds to a testosterone receptor.  Testosterone increases insulin sensitive and thereby reduces the risk for t2d and weight gain, reduces inflammation and convulsive seizures,[7] reduces emotional issues,[8] improves cognitive functions and sexual performance, increases erythropoiesis, reduces risk for CVD and MeS, lowers risk of prostate cancer, and other positive effects.[9]  The variety of benefits come testosterone’s upregulation of autophagy. 


          In the brain it functions not as a steroid, but through neurotransmitter receptors or directly/indirectly as a modulator of neurotransmitters.  Testosterone is converted in the brain to 3-beta androstanediol which is a potent positive allosteric modulator of GABA­A receptors and an agonist of ERbeta.[10] [11]  .  Testosterone functions both as a neurosteroid and a precursor of other neurosteroids and low testosterone and other neurosteroids are CC for neurodegenerative and mental illness, 4:3. 


Neurosteroids, including pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG) and their derivatives [testosterone and estradiol] that are synthesized in the presence of the steroidogenic enzymes [4, 18, 24, 28]. The first step in the biosynthesis of neurosteroids is the conversion of cholesterol to pregnenolone.  Progesterone affects neuronal growth, survival and differentiation, causes regression of neuritic extensions before they have established contact with other neurons or glia, and protects neurons from death induced by picro-toxin [9]” [12]  Neurosteroids are synthetized in the central and peripheral nervous system, particularly but not exclusively in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources.[13]


A table lists the neurosteroids and their protective functions at page 337. Many of the steroid find functions in the brain.  Studies have been done on a number of them because they promote healing following injury, for which progesterone has been the most investigated. 


“Progesterone (PROG) is also a neurosteroid, and a progesterone receptor (PROG-R) has been identified in peripheral and central glial cells.” [14] The article goes on to include neurosteroid functions


The lists and types of benefits for testosterone is long: 


Testosterone, a gonadal hormone, modulates aggressive and sexual behavior (Christiansen, 2001), has anxiolytic and antidepressant-like effects (Carrier et al., 2015), affects cognition (Cherrier, 2005), and regulates synaptic plasticity in the brain (Hatanaka et al., 2015). Moreover, testosterone has been shown to prevent neuronal cell death, to improve memory after damage (Fanaei et al., 2014), and to regulate the activation and reactivity of glial cells upon brain injury (Barreto et al., 2007). The neuroprotective actions of testosterone may in part explain that the decrease in its plasma levels with aging is associated with an increase in neurodegenerative diseases (Bialek et al., 2004; Gold and Voskuhl, 2006; Rosario et al., 2011; Barron and Pike, 2012; Khasnavis et al., 2013). Furthermore, testosterone may be converted into estradiol by aromatase, or dihydrotestosterone (DHT) via 5α-reductase, and part of the protective effects of testosterone might be due to its metabolites (Barreto et al., 2007).[15]


For a longer list of benefits of testosterone with links go to http://healthfully.org/rc/id7.html; for mechanism of protection #4. 


 Because of our western diet there are pathogenic consequences; thus as a neurosteroid, testosterone turns up the heal process for a long lists of signs of the damage caused by the western diet through MTDD and RATP.  Drugs in general don’t repair the causes just modify the behavioral consequences.  The situation is like that of putting air into a flat tire; a better fix is to repair the MTDD though autophagy.  So again I recommend dealing with the basic cause and to undo MTDD.  


          Testosterone functions in the autophagic processes entails that an abnormal reduction such as through castration has significant functional and health consequences;  abnormal low levels pathogenic consequences.[16] [17]  This observation raises an interesting question/puzzle.  There has been over the last 100 years a very significant decline in the level of testosterone among the elderly.  Could this decline be contributing to the divergence in life longevity of men from that of women (averaging about 5 years in most countries on the western diet).  Those with the lowest level die sooner,[18] and is there such an association in the LSPs?   And does HRT for men reduce this difference in longevity?  I have yet to find any longevity studies on point.  Secondly, I aver that this is secondary to MTDD, which could be more significant among men; again I haven’t found studies on point comparing MTDD degrees for the 2 sexes. 




          These chart support my contention that with increasing MTTD many systems are down regulated, and as the InCHIANTI Study (#3) which shows 3 hormonal markers better indicator of morbidity than just one.  This support my thesis that the effects of MTDD effect many system which explains why 3hormones are a better marker than l for MTDD.


In 5:4 are supplements I would take under various situations including testosterone, I do not here wish to drag out the topics related to bad pharma but if you are interested again I refer you to my terse paper on testosterone, which also goes over its benefits, all with links[19] Among them is my observations on testosterone.  For those who wish to read more on the topic, the best in print that I have found is Testosterone for Life by Harvard Professor Abraham Morgentaler, His research and published is published in journal articles, including the tobacco science which is used to scare the public with a warning about prostate cancer.  About the benefits of testosterone, it is similar to estradiol but as an androgen it is and androgen.   


 


6.   Estradiol HRT is healthful:  Estradiol has been well-established as a neuro-protector both for healing following an injury and the prevention of neurodegenerative conditions.  HRT has been shown in men and women to improve cognitive functions. “Newer studies showing rapid effects of estradiol on consolidation of memory through mem brane interactions and activation of inter-cellular signaling pathways are reviewed as well as studies focused on traditional genomic mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and possible actions as a neurosteroid to promote memory are discussed. “ [20] [21]  It has been shown to following a cerebral ischemic event to inhibit apoptosis by increasing autophagic cellular repair.[22]  “It is also protective of mammary epithelial cells (MEC) by a tightly controlled balance be reparative autophagy and apoptosis.” [23]  The many benefits of estradiol is through the upregulating of autophagy.


Electron microscopy revealed that in cells overexpressing EIG121, autophagosomes were markedly increased. Overexpression of EIG121 also increased the cells containing acidic vesicles and induced lysosomal degradation of long-lived proteins. In MCF-7 cells, both EIG121 and LC3 were rapidly degraded by a lysosomal mechanism after starvation.[24]  Our study reveals a unique mechanism through which ERβ/PTEN signaling induces cell death in TCAM2 by autophagy and necroptosis[25]


 


The net result through autophagy is a lower cancer rate, which has been demonstrated with HRT (Europe where Prempro usage was much lower).  Estradiol (EST) reduces the risk of stroke and decreases the incidence and progression of the disease because of its neuroprotective roles in inhibiting cell death that occurs in response to a variety of neuronal stimuli such as inflammation and oxidative stress.” [26] The reason for the reduced apoptosis lies in its alternative, autophagy, which is not easily observed.  Autophagy repairs the cells and thereby reduces the rate of apoptosis.  This is just one of more than 20 benefits I have found from maintaining a youthful level of estradiol and much tobacco science against the natural hormone—at  http://healthfully.org/rc/id2.html--.


          Cancers in women who use HRT are often less advanced, and lower mortality has been reported in those who use HRT than in nonusers.  . . .  The association of HRT with lower proliferation rate and smaller tumor size was exclusively caused by ER-positive tumors.[27]  In a study using estradiol, the most active of the 4-human estrogens and the progestin norethiserone in a tri-cyclic formula (by Novo Nordisc), the results were for 501 women on HRT compared to the control group of 502 confirm


Results:  At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17).[28]


These positive results though better than other studies, follow the pattern that HRT is good for health.


          With the synthetic hormones (other than Prempro, the leading US HRT) the benefits include lower risk of Alzheimer’s disease and other types of dementia, cancers, cognitive decline, CVD, MI, stroke, ischemic events, depression, diabetes, obesity, osteoporosis rheumatoid arthritis, and on the upside are increased sexual satisfaction, mood elevation, firmer breasts, healthier skin (less wrinkles), at http://healthfully.org/rc/id2.html.  A journal article on point is Ten reasons to be happy about hormone replacement therapy: a guide for patients: [29] 


During the last 30 years, there has been an overwhelming number of observational studies demonstrating that HRT protects against ischemic heart disease, osteoporosis, deterioration in cognitive function, colorectal cancer, the reduced incidence of macular degeneration, as well as providing a decided improvement in quality-of-life, such as vasomotor symptoms, urogenital atrophy, insomnia, and general wellbeing.  . . . the risk of death was lower among the HRT survivors; odds ratio 0.28 (95% confidence interval 0.11–0.71). [30] 


Considering that this matching studies with a death rate of just over one fourth of those who didn’t receive HRT, those without metastatic breast as standard treatment should be given HRT, irrespective of without estrogen receptors (ER).[31]  These results and the reports of other benefits follow the pattern of autophagy promoting health.  And the results are far, far better than those for the quasi-estrogens such as tamoxifen.  I can only wonder, given the variety of HRTs used, including the leading Prempro, how much better the results would be for estradiol.  Unfortunately, there are no quality studies of conjugated natural human female hormones, estradiol and progesterone, and that includes for all cancer.[32]  


So what is Pharma’s response to a drug that prevents illness?  To give the flavor of independence and serving the public, there were 2-government funded “landmark” studies to evaluate HRT.  Given the size of the studies and the experts involved, the selection of Prempro, horse estrogens with medroxyprogesterone, the worst of HRTs was deliberate.  The HERS (Heart and Estrogen/Progesterin Replacement Study) and WHI (Women’s Health Initiative were used to overturn the strong evidence supported practice of recommending HRT during menopause and continuing it afterwards because of its many health benefits. 


 




[1] Estradiol like testosterone is when taken orally transported to the liver where it is metabolized, thus estradiol bioactivity is 5% and testosterone even lower.  Progesterone is poorly absorbed, thus and for reasons of patent of exclusivity the synthetic forms of estrogen and progesterone (progestin) are marketed.  Synthetic versions of testosterone have a small percentage of the market, and common form administered is that of a patch constructed in a way to obtain a patent.  The results should be better for the natural hormone with progesterone with estradiol obtain from a compounding pharmacy.  There aren’t studies done on them for financial reasons, they can’t be patented, and the main market through physician has been closed by guidelines, misinformation, and not being covered by insurance companies. 

[2] Guo, wen, Siu Wong, et al, Dec 2012 Testosterone Plus Low-Intensity Physical Training in Late Life Improves Functional Performance, Skeletal Muscle Mitochondrial Biogenesis, and Mitochondrial Quality Control in Male Mice 

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

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

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

[6] Mellon, Synthia, Lisa Griffin, Neurosteroids:  biochemistry and clinical significance

[7] Doodipala, Reddy March 2004, Anticonvulsant activity of the testosterone-derived neurosteroid 3α-androstanediol

[8] Aikey, Jeremy, John Nyby, et al, Dec 2002, Testosterone Rapidly Reduces Anxiety in Male House Mice (Mus musculus)

[9] Saad, F, A. Aversa, et al, July 2013 Onset of effects of testosterone treatment and time span until maximum effects are achieved, this lists many of those benefits and a time line for significant benefits.  A list of from my search of journal articles over a 15-year period with multiple journal links; it is at http://healthfully.org/rc/id7.html. 

[10] Kohtz Amy, Cheryl Frye, Dec 2011, Dissociating Behavioral, Autonomic, and Neuroendocrine Effects of Androgen Steroids in Animal Models, part of the Methods in Molecular Biology

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

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

[13] Cohen, B. H., Gold, D. R., 2001, Cleve. Clin. J. Med. 68, 625 – 626, 629–642 Mitochondrial cytopathy in adults: What we know so far

[14] Baulieu, EE, Nov 1998, Neurosteroids:  a novel function on the brain

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

[16] Serra, Carlo, Nicolae Sandor, et al, Dec 2013, The Effects of Testosterone Deprivation and Supplementation on Proteasomal and Autophagy Activity in the Skeletal Muscle of the Male Mouse: Differential Effects on High-Androgen Responder and Low-Androgen Responder Muscle Groups

[17] Wang, Xian-Jim, Tian-Yuan Xu, et al, May 2015, Castration impairs erectile organ structure and function by inhibiting autophagy and promoting apoptosis of corpus cavernosum smooth muscle cells in rats

[18] Laughlin, Gail, Elizabeth Barrett-Conor, et al, Jan 2008, Low serum testosterone and mortality in older men.  This topic will be developed in #3, which is on a combination of DHEA, testosterone, and IGF-1 levels.  

[19] 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

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

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

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

[23] Holli, K, J. Isola, et al, sept 1998, Low biologic aggressiveness in breast cancer in women using hormone replacement therapy.  Yes, in Europe, because they were using superior HRTs.  In the US Prempro was and still is the best-selling, though it is by far the worst. Prempor is equine estrogen combined with medroxyprogesterone the worst of the progestins.  For much more on the hatchet job  done by NIH with the WHI trial on behalf of pharma.  NIH knowingly chose Prempro, http://healthfully.org/rc/id2.html.  

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

[25] Guido, Carmela, Salvatorer Panza, et al, May 2012, Estrogen receptor beta (ERβ) produces autophagy and necroptosis in human seminoma cell line through the binding of the Sp1 on the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) promoter gene

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

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

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

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

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

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

[32] Judging from repeated reports to me by women, a request for the natural hormones from a compounding pharmacy will likely get a mixture of estrogens; E3 (estriol) which is an antagonist of E2 (estradiol).  I presume it is on the computer program used for prescribing drugs--again I blame bad pharma. The Natural HRT, estradiol plus progesterone is very likely the best combination or with testosterone.  I favor on spotty evidence testosterone and instead of progesterone because of its muscle maintaining effect.  This combination was used in Europe in the 1980s.  Also to be considered in prescribing is the reduced bioactivity with age, thus to multiple by 2 the does adequate for a patient at 30 years to compensate for one over 60 years. According to Goodman and Gilman, the absorption rate is 10% (the figure given for testosterone).



7.  HERS, WHI, horse estrogen and MPA:  “1992, Premarin became the number one prescribed drug in the U.S.”[1]  According to Wyeth (no owned by Merck) it contained 10 estrogen hormones, supra.  The combination of horse estrogen and other steroids has never been carefully tested for safety, and given that Prempro its combination with the progestin medroxyprogesterone (MPA) was the leading HRT, the lacked convincing clinical trials supported the need for a government ran trial, rather than by its manufacturer.  In the 1990s this was provided, the HERS trial addressed the question of cardiovascular benefits in high risk women, followed by a larger trial (WHI) for postmenopausal women.  However, the results could not be extended to the many other formulas of HRT, but they were.  The results of these two trials were contrary to many other prior trials using different products.[2]  Given the press headlines and improper usage of the results following the 2 trials, I can only conclude that this was a well-orchestrated hatchet job of which there are many examples of that type of media orchestration.  This conclusion is reinforced by the fact that in Europe the equine estrogen and its progestin form (with MPA) were not widely prescribed, but the press the treatment and impact upon the use of HRT were the same as in the US.  By now you must be tired of hearing me wave the flag of people harmed. 


The HERS study ran from 1993 until 1998 was of women mean age of 67 who were at very high risk for coronary event (63% of women had a risk higher than 20% over 10 years) and 19% were diabetic. The HERS trial failed to find heart benefits for the post-menopausal women—contrary to a large body of earlier studies.  In an article by a menopausal clinic trashing the HERS study, the authors pointed out that in their clinic the average age was 53, 86% were younger than 60 years.  The press used the HERS study was used to “prove” that estrogen conferred no heart benefits.[3]  The same was done with the WHI (Women’s Health Initiative) study, to which I have in detailed shown that it too was a hatchet job—at /rhr.id19, supra.   The WHI (funded in 1991 and results released in 2002) looked at much more, and though the risks and benefits of Prempro was a wash, the authors of the study concluded that HRT should only be used to control significant unpleasant effects of menopause, and only at the lowest dose for the shortest time.  Over and over again I find that abstracts and conclusions of journal articles differ from the body of the article, and example of such is the articles on the WHI.   Given early studies of Prempro and of MPA (medroxyprogesterone) several critics knew that choice was an assault upon HRT.[4]   


Excerpts from the Scientific American article:  I think that it borders on a tragedy that Premarin and Provera [the 2 compounds in Prempro] were chosen as the only HRT treatments [for the WHI Study]”.  Another researcher finds that Provera [MPA]--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's….  Bruce S. McEwen Neuroendocrinologist of the Rockefeller University is unequivocally critical of the study: "I think that it borders on a tragedy that Premarin and Provera [Prempro} were chosen as the only HRT treatments.". . .  “With medroxyprogesterone [MPA] in Provera you are activating two receptors involved with cell division in the breast," she says, "and that's the culprit, not estrogen [for breast cancer].”  Recent research shows that Provera interferes with estrogen's ability to prevent memory loss and dementia. “Estrogen is able to protect neurons against toxic assaults that are associated with Alzheimer's disease," notes Roberta Diaz Brinton, a neuroscientist at the University of Southern California. . .  she found “that Provera--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's.” . . .   ”This immune response wears away at brain cells and causes them to leak neurotransmitters such as glutamate, which overloads and kills neurons.” [5]  


Is Nature ignorant of the vital fact that Prempro contains no progesterone, but instead the artificial progestogen Provera [MPA].  The other component is Premarin (conjugated estrogen), which is a very uncertain, patent mixture of substances from the urine of pregnant mares…. [equine estrogens] have crucially different effects.  Prempro is totally unrepresentative of any other product used for HRT purposes….  Much of it was known before the NIH chose to use Prempro in its intended landmark study.  Using a study of the effects of Prempro to attack the entire use of HRT has, through needless fear, caused millions of women to forgo considerable benefits of HRT using better products.  This point has been repeatedly made by endocrinologists.   Why does Nature not know it?--END OF ARTICLE.[6]


The critics get their day in the journals, then the details of their critique are forgotten, and the message by pharma is remembered by over 90% of physicians and a greater percentage of the public, “sex hormones have life-threatening risks”.  A 1999 study indicated that 38% of women between 50 and 74 years.[7]  As of 2019, the number in that age group using estradiol is under 5% for that age group; pharma has changed the practice of medicine again.  Among pharma’s tools in addition to tobacco science are the clinical guidelines which form a barrier to block what is in patient’s best interest.  Physicians will not recommend HRT; their patient asks for it.  Guidelines and their clinic’s standard of treatment form a second effective hormonal barrier.  Physicians who fall short of the administrative quotas are at risk of losing employment.                  


A physician who recommends estradiol for osteoporosis or hot flash, and is taken to court for breast cancer, though natural estrogen of progesterone lowers the rate, his attorney cannot argue that point because expert opinion in the guidelines using the WHI and other studies claims HRT promotes breast cancer and approves different medications.  The Supreme Court in the U.S. has ruled that when there is a consensus of expert opinion, the defendant cannot argue that the consensus is wrong.  Giving advice in the best interest of the patient has been buried by tobacco science, guidelines, and the Supreme Court.  The silver spike is that often the insurance company do not list natural HRT in in their formulary.        


Add to this that pharma is very good at behavioral control through perks, CME classes, handouts of articles, and establish a religious like faith is their mantra, safe and effective.  Pharma has succeeded in turning physicians into pill pusher.  Few doctors are willing to be outsiders in our age of miracle drugs.  For very possible the best 5-page account of why doctors are pill pushers, and it is sympathetic to their situation go to http://healthfully.org/rep/id11.html.  


This work on CAWD and autophagy has taken me full circle for I have come back to my early extensive review of the sex hormones done between 2004 and 2006 for https://healthfully.org/fhr  and /malehormones, these results of my first review of the literature gave me my first strongly supported example of how pharma with its lapdogs the FDA and corporate media were promoting profits over health, while selling their results as protecting the public and promoting health.  The early studies on the benefits of HRT were not wrong, not overturned by a studies of Prempro (horse estrogen and medroxyprogesterone).[8]  I had listened to Prof. Robert Langer explain to a large audience in 2003 at UCSD’s medical school that the results of the WHI (Women’s Health Initiative using Prempro) couldn’t be extended to other formulas of HRT.  My review of the topics confirmed his statements.  The consequences of replacing what works with what doesn’t has a very personal negative my mother and my father concerning their health and quality of life and convinced me of the importance of treating low testosterone (#14).


And it is not only estrogen and some of the other steroid hormones[9] that turns up autophagy and lowers the risk for cancer.  The major Harvard’s Nurses’ Study[10] found that daily aspirin very significantly increased the survival of breast cancer for those who weren’t stage 4.  Both estradiol and aspirin (2:5, 5) promote autophagy,[11] thus apoptosis its other benefits.[12]  I was started on 8 aspirin a day (325 mg enteric coated in 1992 to treat chronic back pain).  After finding out in 1993 based on a University of Toronto population study, that aspirin reduced the risk by over 50% for colon cancer, I continued with 1 to 2 aspirin up to this present day—now uncoated because of low absorption rate for the coated aspirin which takes 8 hours for peak level with a meal.


The criticisms are buried by time:  consider the evolution of the Wikipedia article on the Women’s Health Initiative study (WHI is the second major piece of tobacco science); the article has slowly evolved to mirror the teachings fed doctors and public about HRT.  The same crapola is repeated in the Wikipedia article on HRT, which misuses the WHI trial.[13]  The current Wikipedia article for the WHI study makes no mention of equine estrogen or that medroxyprogesterone blocks some of the benefits of estrogen.[14]  The early critics like Prof. Langer are ignored, as too all the earlier studies which supported a much different outcome.  Over and over again I read in journals how the WHI study with a budget of $625 million his the gold standard.[15]  So what are their figures for WHI?  Note, AR is events per 10,000 person years.  Prempro increased coronary heart events (1.24, AR +6), strokes (1.31 AR +8), pulmonary embolism (2.13 AR +10), breast cancer (1.24 AR +8), dementia, (2.05),* and gallbladder disease (1.59)* which are contrary to earlier studies that excluded Prempro.  The plus side for Prempro balanced out those negative effects in that the total mortality dropped slightly (0.98, AR -1), hip fractures (0.67, AR-6), all factures (0.76, AR -47), colorectal cancer (0.66, AR -7), endometrial cancer (0.81, AR -1), diabetes (0.70).*  The asterisk is for those which there are no AR figure.  Since the study 2002, both type 2 diabetes and dementia have over doubled, thus AR figures for Prempro would clearly justify its usage and that of all the other HRTs.  Need I again comment about how Wikipedia relies upon KOLs?  And what is echoed by Wikipedia is supported by sources that all receive funds from pharma and others relying on expert opinion.[16]  Unfortunately, most readers assume that hormones are bad, I hope you who don’t know better will hear the wake up bells of Marcia Angell and Peter Gotzsche.[17] 


 


8.  Osteoporosis and estrogen; 


 


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


General structure of bisphosphonate


https://upload.wikimedia.org/wikipedia/commons/9/91/615_Age_and_Bone_Mass.jpg


 


As one doctor told me in 2005 commenting on the WHI:  “There goes the effective treatment for osteoporosis.”  This is a major health disaster because a good treatment has been replaced by one which long-term does more harm than good.  Having eliminated the competition of HRT, the 2001 numbers for fractures in postmenopausal women have more than double.  The lifetime risk of symptomatic fracture for a 50‐year‐old Caucasian man in the UK has been estimated to be 2% for the forearm, 2% for the vertebra and 3% for the hip, whereas the corresponding figures for a 50‐year‐old woman are 13%, 11%, and 14%, respectively.” [18]  Osteoblasts have both estrogen and testosterone receptors for a reason.  Again we have pharma orchestrating a stampede for profits.


The female sex estrogen deficiency following menopause or surgical removal of the ovaries is correlated with a rapid reduction in bone mineral density, while in men, a decrease in testosterone levels has a comparable (but less pronounced) effect” [19]  Osteoporosis and osteoporotic fractures are generally considered to mainly affect older postmenopausal women, but up to 20% of symptomatic vertebral fractures and 30% of hip fractures occur in men.  . . . One of the major secondary causes of osteoporosis in men is hypogonadism”[20]Male patients affected by rheumatoid arthritis[21] have been shown to possess low serum testosterone” [22] and a  similar finding for osteoarthritis.  Compared to women, the decline in men is gradual.[23]   These declines in men and women are more than mere association, a wide variety of evidence shows the relationship to be causal.    


One reason for the assault upon the estrogen in is a class of drugs known as bisphosphonates.  This assault extend to DHEA, since it too lowers the risk for osteoporosis.[24][25]  Progesterone also is effective in preventing osteoporosis.  Progesterone also has been proven very effective at preventing osteoporosis and reversing it.[26]  Very possible there is a similar to the results of the InCHIANTI study, the combination of hormones is better than just estradiol.  Most of the biological pathways involve several hormones—a fine tuning of the regulatory process.  Research has shown that estradiol doesn’t promote bone remodeling, rather it slows the loss of bone (calcium) and it is the progesterone that promotes calcium absorption; they function as a team.  For men it is testosterone and estradiol that function as a team (low testosterone entail low estradiol, since some of the testosterone is converted to estradiol).  But first let us look at what pharma has done based upon hormonal hysteria, the bisphosphonate treatment. 


Pharma replaced nature’s way with bisphosphonate, and then showed it increased bone density—ultimately for marketing by use of the surrogate endpoint of density and a very modest reduction short-term in fractures (need I again mention fraud in trials?). [27] Bisphosphonates consist of 2 polar phosphate groups, which are absorbed by the bones. But this group--as one should expect--doesn’t function as well as calcium compounds.  They don’t make the bones stronger, just denser. 


Density doesn’t equate either to less brittle. Children for example have less than half the density of adults.  At age 3 the average male TBLH (total body less head) BMD in grams per/cm2 is 0.3; at 5 0.46; at 9 0.63, 15 0.85, and 18 years 0,95; and females at 18 years is 0.75.[28] By the age of 80 the average is about the same as an 8 year old.  But given the great difference in frequencies of fracture, the association of density with fracture fails to capture the brittleness of the senior’s bones.  Moreover, bone mass is controlled by a hemostatic system that tends to return to a set point after any perturbation.[29]


          The very mechanism by which bisphosphonates modestly contributes to bone density explains why their biased claim of benefit is slim, and gets worse the longer the study is run.[30]  It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes.” [31]  “The inhibition of protein phenolation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis.” [32]  By the bisphosphonates increasing apoptosis of osteoblasts rate increases the overall decline in osteoclast activity results in brittle bones.  The fix isn’t what guidelines call for, that of adding phosphate groups to the bone, or other foreign compounds.


There is evidence from animal studies that with prolonged alendronate [Fosamax] use, bones become more brittle and susceptible to fracture. Unfortunately, it is currently unknown at what point that occurs in people.  . . . When used for secondary prevention of fractures (subsequent fractures), the number of women who would need to be treated with alendronate for five years to prevent one hip fracture was 100.  . . . Severe ulcers in the esophagus is a well-documented hazard.[33]   Atrial fibrillation, an irregular and rapid heartbeat, is a newly recognized risk being investigated by the Food and Drug Administration.  . . . Osteonecrosis of the jaw (destruction of the jaw bone) is a very serious complication.  . . .  Lastly, incapacitating bone, muscle and joint pain is another known hazardous side effect of bisphosphonates.[34]  And the best treatment, based on the WHI study is the main justification the warning against estrogen:  “Furthermore, the ACP recommended against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene (Evista) for the treatment of osteoporosis in women. This was graded as a strong recommendation with moderate-quality evidence.” [35]


We have another case of good drugs off-patent (hormones) being replaced by drug (bisphosphonates) which are worse than nothing at all.  If only the governments would open up their data banks so that we can now how much worse real world patients are doing on the patented drug.


Has anything changed? current guidelines: 


“The American College of Physicians (ACP) has recommended in an evidence-based clinical practice guideline(annals.org) that physicians offer pharmacologic therapy with a bisphosphonate -- alendronate (Fosamax), risedronate (Actonel, Atelvia) or zoledronic acid (Reclast) -- or the biologic agent denosumab (Prolia) to reduce the risk for hip and vertebral fractures in women who have known osteoporosis.[36]  


The situation gets complex, and as stated in the 2nd paragraph of this section, relying upon the lead of the InCHIANTI Study, the combination of hormones is better than one.  Important results are submerged in the sea of journal articles.[37]  it isn’t only estradiol that contributes to a positive bone remodeling but the combination with progesterone.  Estradiol promotes bone reabsorption and the same for testosterone.  The supplement of estradiol by itself diminishes the rate of calcium absorption from the bones and progesterone promotes the utilization of calcium to build new bones.  Testosterone works with estradiol in men to halt the loss of bone calcium.[38]    


It took me 15 years of researching estradiol and testosterone, from 2004 until 2015 to find out about the current combination. Moreover, I had read the Goodman and Gilman 1981 Edition of The Pharmacological Basis of Therapeutic in the early 1980s and its role in promoting “last only 9 to 14 months” and the next paragraph “only 25% of women postmenopausal patients develop osteoporosis and treatment with calcium salts is as or more effective than routine prophylactic use of estrogen is more difficult to justify” P. 1431.  However, the use of calcium supplement in quality studies has been shown to be ineffective because it has no effect upon the hormone control of remodeling.  As for duration of benefit, it is continuous.  The roots for the Prempro attack upon HRT goes back to this book and undoubtedly before “However all estrogenic materials can cause the more serious cardiovascular and perhaps tumorigenic effects” P 1428.  No mention is made of the role of progesterone’s role in remodeling.  It should have been highlighted in Wikipedia, and mentioned in a number of journal articles on osteoporosis or the benefits of HRT in the introduction or discussion section. 


Reading extensive hundreds of journal articles on the 2 major sex hormones and other related hormones, I only came across the statements of their synergistic effect on bone remodeling.  Then after 15 years, I became aware that estradiol slows the resorption of calcium of the slowing of the loss of calcium nor had I read that progesterone increase in the rate of absorption for building bones.  Nor in my preparation for a review of progesterone did I find references to osteoporosis; its calcium references were about calcium signalling. 


Kinetic and histomorphometric data suggest that bone formation and resorption are closely linked (3, 4). Increased resorption, which occurs after the menopause, will not cause a net loss of bone if formation is equally increased.  Studies of bone histology suggest that bone formation in postmenopausal women is not increased but is inappropriately “normal” or low (5, 6). Estrogen treatment is associated with decreased resorption and with no change or a slight decrease in formation (5, 7). The long term net response to estrogen therapy appears to be decreased remodeling and the creation of a relatively inactive bone mass (5–7). Despite Albright's assumption that estrogen deficiency caused decreased bone formation, it is now clear that estrogen's predominant effect is to decrease bone resorption.” [39]  Fuller Albright's observation that women developed osteoporosis after, but rarely before the menopause, led him to assert that osteoporosis was caused by hormonal changes around the time of the climacteric (1). Although his first clinical trial tested progesterone and testosterone, as well as estrogen treatment, Albright believed that it was estrogen deficiency that resulted in decreased bone formation and caused osteoporosis, “a condition in which the osteoblasts were primarily deficient in laying down osteoid tissue” (2).” [40]


The combination of the two hormones work together for healthy bones, using just estradiol would result in the accumulation of older osteoblasts.  Something is very wrong when role of progesterone is left to obscurity, thus the use of estradiol is not enhanced.  I wonder who benefits from ignoring the role of progesterone?  This follows the usual pattern of tobacco ethics.[41]    


These studies of the steroids, that progesterone plays, as to bone health, is one of several significant healthful roles.  We shall find out another major piece to the puzzle concerning bone formation and remodeling is the replacement of collagen (4:4), to which low ascorbic acid and MTDD are involved in the pathogenic processes.  Evolution has fined tuned the process of remodeling, and the closer we can follow its path the healthier we will be (pharma eat your marketing hat).[42] 


I take very personal what happened to my mother who had the age of 91 had her 3rd bone break.  She spent two days on the floor of her apartment, until someone heard her banging on the floor and came to investigate.  The next two years at great expense she spent on her back unable to move.  Finally, the friend of old people, phenomena, in three days ended her low quality life. 


Fosamax, which she took for and prior Aredia for a decade makes bones brittle; it doesn’t promote bone remodeling.  She is one who will take every pill her doctor gives; however, she stopped taking Fosamax 4 years before her hip break because of side effects.   She did go back on to Aredia (pamidronic acid) for that too caused nausea.  No, I am not angry at pharma, for the companies play by the capitalist rule of profits before people.  


I am a Benthamite, a utilitarian and thus known that the ideal system to rational guide behavior is to have each person try to maximize the well-being of all people.  The problem isn’t the people, but what shapes their behavior.  My roots go back to Plato as voiced[43] in his The Republic and Epicurus’ maxims. 


 


9.  Epidemic of osteoporosis and osteoarthritis:  What is driving the bone on bone joints and bone breaks?  One part, as by now you expect, is the B-4 and the lack thereof in LSPs of those conditions.  Down-stream is the hormone levels of the elderly,[44] the rancid, oxidized fats in cell membranes, delayed replacement of collagen, problem a sensitivity to uric acid, medications, and others whom I have yet to uncover.  The role of drugs founds some light in a Wikipedia list.  I have been warning for about 12 years about protein pump inhibitors, but their list is much longer.


Certain medications have been associated with an increase in osteoporosis risk; only glucocorticosteroids and anticonvulsants are classically associated, but evidence is emerging with regard to other drugs.



The two are additive, the chemicals and the B-4 and all that follows from B4, such as the folding of collagen. 


      The low hormones are a CC to the RRA and RATP that is causing the epidemic of arthritis; “there are over 100 types of arthritis.  . . . [i]n the United States more than 20% have a type of arthritis.”[46]  “Population studies indicate the extremely high prevalence of OA (over the age of 70 up to 90% of the [female] population have some radiological evidence of OA)”.[47]  Free and serum testosterone levels were significantly lower in the RA males than in either the AS [ankylosing spondylitis] group or the healthy controls”[48]  Moreover, improvements have been shown with the administration of testosterone.  Similar results for estrogen and progesterone.  With our high sugar diet and thus the B-4, the decline in sex hormones that has steadily increased over the last 100 years (graph #4) and I assume the same for testosterone’s sister the estrogens, we have over two-thirds the population above 70 experience joint pains and worse.  We have another class of illness that is virtually unknown for the LSPs, and was 200 years ago only a condition of affluence.   


 




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

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

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

[4] Premarin came on the market in 1942, and name comes from mare, for which equine estrogen is derived from mare urine.  # decades later medroxyprogesterone (Provera) was added and the combo called “Prempro”, conjugated estrogen and MPA. 

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

[6]    Michaels, ANNA, Sept 2010.  My link to the original article goes to a different page in Nature, an article claiming that pharma’s ghost writers have downplayed risks of HRT, at http://www.nature.com/news/2010/100907/full/news.2010.453.html#comment-id-13486.  A business switch in articles made by the editor of Nature with approval of pharma.  Though the industry attacks HRT, those that manufacture it won’t pull it from the market, though they all too often come out with new version that is too low a dose or in other ways minimally effective, such as enteric coated low-dose aspirin.  It is all governed by profits.

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

[8] A bit of history:  “Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an 8-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet.[52] It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium.[52] This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera).[52]   Wiki HRT April 2019.  Again, apply the results of an increase in endometrial cancer to horse estrogen, the results don’t extend to estradiol.  I am not aware of an association with estradiol.

[9] In their sections, DHEA and Testosterone lower the rates of cancer, which is what to be expected given their upregulation of autophagy.  What of pregnenolone, progesterone, and IGF-1

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

[11] Din, Farhat, Asta Valandiute, et al, June 2012, Aspirin Inhibits mTOR Signaling, Activates AMP-Activated Protein Kinase, and Induces Autophagy in Colorectal Cancer Cells

[12] Pietrocola, Federico, Francesca Castoldi, et al, Feb 2018, Aspirin recapitulates features of caloric restriction.  Caloric restriction lowers glucose and insulin level and increases autophagy and lippolysis.

[13] Wiki hormone replacement therapy April 2019, and

[14] Adams, Michael, Thomas Registor, et al, Feb 1996, Medroxyprogesterone Acetate Antagonizes Inhibitory Effects of Conjugated Equine Estrogens on Coronary Artery Atherosclerosis  Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis,. . . . Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P<.004). . . . MPA-associated antagonism. . . . oral CEE [continuous equine estrogen] inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this athero-protective effect.

[15] Particularly annoying I s the calm of reward from the WHI study “A 2014 analysis calculated a net economic return on investment of $37.1 billion for the estrogen-plus-progestin arm of the study's hormone trial alone, providing a strong case for the continued use of this variety of large, publicly funded population study.” Wiki WHI April 2014, in Roth, Joshua, Ruth Etzioni, et al, May 2014, Economic Return From the Women’s Health Initiative Estrogen Plus Progestin Clinical Trial, A Modeling Study The over 100 million women harmed in the US alone over the last 15 years by not taking HRT is written up as a benefit using WHI tobacco science.  Sad, the crap we are fed as good, like the lead compound that once was frequently added to wine until the 1700s to improve its flavor.  Marketing needs to be barred from science to prevent a sweat words hiding harm.     

[16] “Evidence to support long term use however is poor.” Quote from Wikipedia based on the Position of the North American Menopause Society. March 2012 The 2012 Hormone Therapy Position Statement of The North American Menopause Society. They relied on the WHI study with no mention Prempro for their series of warning concerning risks versus limited benefits.   

[17] If I was a god, I would castrate every surgeon who in doing a hysterectomy has taken sound ovaries—only joking.  This would be divine Judeo justice.  PS, I am a utilitarian and therefor retribution is immoral.   

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

 [19] Wiki, Osteoporosis, April, 2019.  I do not recall factures in women being a major concern in the 1950s and 60s.    

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

[21] Cutolo, Maurizio, Enrico Balleari, et al  Oct 1998, Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation

[22] Cutolo, Maurizio, Enrico Balleari, et al  Oct 1998, Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation

[23] The putative heart benefit of estrogen evaporates with the LSPs in that the elderly of both sexes are CVD free.  See Taubes The case against sugar, where he describes the first case of a Nigerian with CVD.  He was educated in England in law and became in Nigeria a Supreme Court Justice; thus Western diet caused his CVD. 

[24] Scott, A, K. Higdon, et al, Jan 2001 The prevention of osteoporotic progression by means of steroid loaded TCPL drug delivery systems.  that DHEA may possibly be used in postmenopausal patients to reduce osteoporotic progression.”

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

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

[28] Liu Junjting, Liang Wang et al, May 2017, Bone mineral density reference standards for Chinese children aged 3–18: cross-sectional results of the 2013–2015 China Child and Adolescent Cardiovascular Health (CCACH) Study.  In the study there were figures for the US NHANES study

[29] Gafni, Rachel, Jeffrey Barron, March 2007, Childhood Bone Mass Acquisition and Peak Bone Mass May Not Be Important Determinants of Bone Mass in Late Adulthood

[30] For those who wish to know more about the fractured clinical trial system, I recommend Prof. Ben Goldacre’s Bad Pharma. ”Ben Goldacre is a founder of the campaign and its [AllTrials] most public spokesperson. In 2016 he participated in the launch of the OpenTrials database. AllTrials is an international initiative of Bad Science, BMJ, Centre for Evidence-based Medicine, Cochrane Collaboration, James Lind Initiative, PLOS and Sense About Science and is being led in the US by Sense About Science USA, Dartmouth’s Geisel School of Medicine and the Dartmouth Institute for Health Policy & Clinical Practice”.. , , , As of May 2017, The AllTrials petition has been signed by 90,282 people and 721 organisations.  Wiki AllTrials, April, 2019.

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

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

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

[35] Supra

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

[37] Over and over again I find evidence that should be broadcast lost in that sea, such as very high dose of aspirin reversing T2DM, cholesterol is produced at night, therefore, why take a stain or niacin during the day?  Enteric coated aspirin takes 8 hours for peak serum level, compared to under an hour for uncoated aspirin, and on and on as you can tell by my digressions. 

[38] Falahati-Nini, Alireza, B. Riggs, et al, Dec 2000, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. FULL We conclude that in aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation.”

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