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6:2 HORMONAL HEALTH

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

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




  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 their functions in the mitochondria promotes a weakening of the immune system and thus to promote the infectious concequense which is what the LSPs in the pre-electric world die from.  Sex hormones in the broader family are a vital part of an optimally operating autophagy system.  Of particular interest are the sex steroid testosterone, dihydrotestosterone, estradiol, androgens, and their structurally related steroids:  of these I have reviewed in depth the literature on the sex hormones, pregnenolone,[1] DHEA, and progesterone along with the growth factor IGF-1 and IGF-2. The chart of above gives you some idea of the number of sex hormones, and thus the Herculean task of sorting out their functions and interactions. 

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

    They are synthesized in the gonads, adrenal cortex, and some other tissues including in the brain by the glial cells.[3]  Because pharma frames the topic, their function as neurosteroids has been burried.[4]  Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester may improve cognitive and memory function. In addition, they may have protective effects against schizophrenia.” [5]  There are many other health benefits independent of autophagy, such as neurosteroids, androgen effects, lipo regulators, mitochondrial functions, etc. There is much to gain from understanding their importance of these steroids.  Given the many functions of the steroids made from cholesterol, the war on cholesterol and these steroids is another example of pharma profiting from illness.  I shall let the evidence do the talking.  Nature doesn’t evolve such a large number of steroids to harm mammals. 


Yes, again we have a case of pharma promoting illness and again I am responding to the harm done.  Again we have pharma tell us that something which is healthful causes illness and framing the topic for their ends.  Again we have pharma “proving” that nature’s systems making us sick, in this case with the sex hormones.[6]  And again there is a mountain of journal articles proving the opposite.  This chapter both exposes their crapolla and also supports theme in this Section of the healthful fixes.  Natural hormones are very healthful; and low levels are associated with age related conditions and morbidity both in LSPs and HSPs.  They are more than merely a marker, because natural hormones play key homeostasis functions and autophagy.   


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


I am focusing on estradiol, DHEA, and testosterone, since there is strong evidence for their health benefits.  The cancer association is the work of bad pharma.[10]  I had for 15 years settled for association of the health benefits of these 3 hormones[11] now I found the why.  I went from prevention happened in the black box, to a rough diagram of the workings of the black box.  If they are so good they should extend life. 


 


2.  InCHIANTI Longevity study:  Relying on the InCHIANTI Study of men followed 6 years, the cohort with the lowest 1/4th of all 3, testosterone, DHEAS, and IGF-1 (insulin like growth factor 1—there are 2) had a death rate of 2.44 higher than the 3/4th above them.[12] 


Several lines of evidence suggest that the aging process is associated with a decline in anabolic hormones and increase in catabolic hormones.22 In this study, we evaluated the 3 key anabolic hormones: bioavailable testosterone, DHEA-S, and IGF-1. Each of these anabolic hormones has a direct impact on lipid and glucose metabolism.23-25  evidence has indicated that low testosterone, IGF-1, and DHEA-S levels are good predictors of cardiovascular disease and diabetes in men.5,10,26 Furthermore, we have previously shown that a low testosterone level is inversely related with inflammatory markers and predicts the development of anemia in the older population.27,28 Both cardiovascular disease and anemia are 2 independent predictors of mortality in older men.29  … Compared with men with levels of all hormones above the lowest quartile, men with 1, 2, or 3 hormones in the lowest quartile had an HR for mortality of 1.47 (95% CI, 0.88-2.44), 1.85 (95% CI, 1.04-3.30), and 2.29 (95% CI, 1.12-4.68) (test for trend, P = .006), respectively (Table 2). After adjusting for confounders, including age, BMI, educational level, smoking, alcohol and caloric intake, physical activity, log (IL-6) levels, and chronic disease such as diabetes, hypertension, peripheral artery diseases, coronary heart disease, congestive heart failure, stroke, Parkinson disease, COPD, asthma, and cancer, the HRs for mortality were 1.04 (95% CI, 0.56-1.95), 1.34 (95% CI, 0.67-2.65), and 2.44 (95% CI, 1.09-5.46), respectively (test for trend, P <.001) (Table 3).  [to have all 3 in the lowest 25% entail after adjusting for existing confounding variable a 2.44 death risk above the first 3 groups.  In other words, the healthies of the low hormones still died at a much higher rate than the healthiest of the 75% group].  . . . The mortality rates (events per 100 person-years) were 2.9 in group 0, 6.2 in group 1, 16.7 in group 2, and 46.0 in group 3 (P = .007, test for trend).[13]


This raises the question as to how the 2 sex hormones and IGF-1 can be associated with health, and thus life extension.  The connection of testosterone[14]  and estradiol with autophagy comes in many directions, and there are other healthful effects for the sex hormones.  Given the difference of only one functional group and a ring structure, explains why both through autophagy have the same benefits.[15] [16]   DHEA and IGF-1 will be discussed at the end of this subsection.   Note:  based on my extensive review of the literature I am assuming that estradiol, if women were included in InCHIANTI study, would have resulted in similar positive result.  Including estradiol.  So what are the benefits and why? 




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

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

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

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

[5] Wiki, neurosteroids, Sept 2019

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

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

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

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

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

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

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

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

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

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

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

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







3.       Sex hormone benefits: 

    TESTOSTERONE                              ESTRADIOL   


  


                                DEHYDROEPIANDROSTERONE

                                          



  

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


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


 


UTI,  NFALD, and venus thrombosis for E2, look them up for TTT  More from the two rc/ articles


 


     


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


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


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


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


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


 


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


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


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


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


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


The lists and types of benefits for testosterone is long: 


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


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


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


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




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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

                        

  


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


In 5:4 are supplements I would take under various situations including testosterone, I do not here wish to drag out the topics related to bad pharma but if you are interested again I refer you to my terse paper on testosterone, which also goes over its benefits, all with links[1] Among them is my observations on testosterone.  For those who wish to read more on the topic, the best in print that I have found is Testosterone for Life by Harvard Professor Abraham Morgentaler, His research and published is published in journal articles, including the tobacco science which is used to scare the public with a warning about prostate cancer.  About the benefits of testosterone, it is similar to estradiol but as an androgen it is and androgen.   


 


6.   Estradiol HRT is healthful:  Estradiol has been well-established as a neuro-protector both for healing following an injury and the prevention of neurodegenerative conditions.  HRT has been shown in men and women to improve cognitive functions. “Newer studies showing rapid effects of estradiol on consolidation of memory through mem brane interactions and activation of inter-cellular signaling pathways are reviewed as well as studies focused on traditional genomic mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and possible actions as a neurosteroid to promote memory are discussed. “ [2] [3]  It has been shown to following a cerebral ischemic event to inhibit apoptosis by increasing autophagic cellular repair.[4]  “It is also protective of mammary epithelial cells (MEC) by a tightly controlled balance be reparative autophagy and apoptosis.” [5]  The many benefits of estradiol is through the upregulating of autophagy.


Electron microscopy revealed that in cells overexpressing EIG121, autophagosomes were markedly increased. Overexpression of EIG121 also increased the cells containing acidic vesicles and induced lysosomal degradation of long-lived proteins. In MCF-7 cells, both EIG121 and LC3 were rapidly degraded by a lysosomal mechanism after starvation.[6]  Our study reveals a unique mechanism through which ERβ/PTEN signaling induces cell death in TCAM2 by autophagy and necroptosis[7]


 


The net result through autophagy is a lower cancer rate, which has been demonstrated with HRT (Europe where Prempro usage was much lower).  Estradiol (EST) reduces the risk of stroke and decreases the incidence and progression of the disease because of its neuroprotective roles in inhibiting cell death that occurs in response to a variety of neuronal stimuli such as inflammation and oxidative stress.” [8] The reason for the reduced apoptosis lies in its alternative, autophagy, which is not easily observed.  Autophagy repairs the cells and thereby reduces the rate of apoptosis.  This is just one of more than 20 benefits I have found from maintaining a youthful level of estradiol and much tobacco science against the natural hormone—at  http://healthfully.org/rc/id2.html--.


          Cancers in women who use HRT are often less advanced, and lower mortality has been reported in those who use HRT than in nonusers.  . . .  The association of HRT with lower proliferation rate and smaller tumor size was exclusively caused by ER-positive tumors.[9]  In a study using estradiol, the most active of the 4-human estrogens and the progestin norethiserone in a tri-cyclic formula (by Novo Nordisc), the results were for 501 women on HRT compared to the control group of 502 confirm


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


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


          With the synthetic hormones (other than Prempro, the leading US HRT) the benefits include lower risk of Alzheimer’s disease and other types of dementia, cancers, cognitive decline, CVD, MI, stroke, ischemic events, depression, diabetes, obesity, osteoporosis rheumatoid arthritis, and on the upside are increased sexual satisfaction, mood elevation, firmer breasts, healthier skin (less wrinkles), at http://healthfully.org/rc/id2.html.  A journal article on point is Ten reasons to be happy about hormone replacement therapy: a guide for patients: [11] 


During the last 30 years, there has been an overwhelming number of observational studies demonstrating that HRT protects against ischemic heart disease, osteoporosis, deterioration in cognitive function, colorectal cancer, the reduced incidence of macular degeneration, as well as providing a decided improvement in quality-of-life, such as vasomotor symptoms, urogenital atrophy, insomnia, and general wellbeing.  . . . the risk of death was lower among the HRT survivors; odds ratio 0.28 (95% confidence interval 0.11–0.71). [12] 


Considering that this matching studies with a death rate of just over one fourth of those who didn’t receive HRT, those without metastatic breast as standard treatment should be given HRT, irrespective of without estrogen receptors (ER).[13]  These results and the reports of other benefits follow the pattern of autophagy promoting health.  And the results are far, far better than those for the quasi-estrogens such as tamoxifen.  I can only wonder, given the variety of HRTs used, including the leading Prempro, how much better the results would be for estradiol.  Unfortunately, there are no quality studies of conjugated natural human female hormones, estradiol and progesterone, and that includes for all cancer.[14]  


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




[1] 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

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

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

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

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

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

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

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

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

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

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

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

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

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




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


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


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


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