FEMALE HORMONE REPLACEMENT

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This article explains the main mechanism by which women extend life with HRT, and conversely die sooner with less estradiol.  The main mechanism is through estradiol promoting anti-oxidation production, which thus lowers the risk of numerous chronic age related conditions.  Others positive effects from HRT include bone remodeling which prevents osteoporosis, mild androgen affect through conversion of about 10% to testosterone, which prevents sarcopenia prevent loss of muscle.  The anti-inflammatory effect reduces the risk of rheumatoid arthritis.  The greatest life extension comes through the prevention of cardiovascular disease, which comes mainly through the anti-oxidation and down regulating the immune response and thereby reducing atherogenesis and thus cardiovascular disease.  For a complete list of benefits, why pharma’s HRT are significantly inferior to natural HRT, the junk science used to limit HRT usage, and recommendation for natural HRT go to http://healthfully.org/rc/id2.html .   

http://www.sciencedirect.com/science/article/pii/S0014579305004540 doi:10.1016/j.febslet.2005.03.090

Why females live longer than males? Importance of the upregulation of longevity-associated genes by oestrogenic compounds

Abstract

Females live longer than males in many mammalian species, including humans. Mitochondria from females produce approximately half the amount of H2O2 than males. We have found that females behave as double transgenics overexpressing both superoxide dismutase and glutathione peroxidase. This is due to oestrogens that act by binding to the estrogen receptors and subsequently activating the mitogen activated protein (MAP) kinase and nuclear factor kappa B (NF-κB) signalling pathways. [Some] Phytoestrogens mimic the protective effect of oestradiol using the same signalling pathway. The critical importance of upregulating antioxidant genes, by hormonal and dietary manipulations, in order to increase longevity is discussed.

 1. Introduction: Females live longer than males in many species including humans

Females live longer than males in many mammalian species. For instance, male Wistar rats, in our laboratory, have an average life span of 24 months whereas females median life span is 29 months, i.e., 14% more than in males (Table 1). Of the most importance, the same happens in humans. In Europe, the average life span is 73.7 years for males and 83.8 years for females [1]. The fact that this difference occurs in animals as well as in humans, indicates that the difference cannot be attributed to sociological differences but rather to specific biological characteristics of both genders.


Males

Females

Females/males (%)

Average life span (months)

24 ± 0.5

29 ± 0.6

121

Mitochondrial H2O2production (nmol/min mg prot)

•Liver

0.10 ± 0.03**

0.07 ± 0.02

70

•Brain (non-synaptic)

0.08 ± 0.02*

0.04 ± 0.02

50

•Brain (synaptic)

0.29 ± 0.04*

0.17 ± 0.06

59

Reduced glutathione (GSH) (nmol/mg prot)

6.4 ± 0.9*

9.8 ± 1.8

153

Mitochondrial DNA damage (8-oxo-dG/100 000 dG)

55 ± 5**

15 ± 8

27

Mn-superoxide dismutase

•Expression (arbitrary units)

3.1 ± 0.9*

6.5 ± 1.8

210

•Activity (U.I./mg prot)

34 ± 8**

74 ± 18

218

Glutathione peroxidase

•Expression (arbitrary units)

2.6 ± 0.3**

5.4 ± 0.3

208

•Activity (U.I./mg prot)

0.18 ± 0.06**

0.51 ± 0.01

283

16S ribosomal RNA

Expression (arbitrary units)

1.7 ± 0.4**

6.4 ± 0.3

376

2. The mitochondrial theory of ageing: mitochondria are key organelles for the cellular production of oxidants in ageing

The free radical theory of ageing was first introduced by Gerschmann et al. [2] and by Harman [3] in the 1950s. An important feature of this theory is that it provides a rationale for intervention, i.e., administration of antioxidants may decrease the damage associated with ageing. In 1980, Miquel [4] introduced a further development of this theory, pointing to the role of mitochondria as source of free radicals and as a target of oxidative damage in the ageing cell. We reported that mitochondria are damaged inside the ageing cells [5]and that administration of antioxidants partially prevents age-associated oxidative damage [6] and [7]. Thus, mitochondria are key organelles to study the possible reasons for the different longevity between genders.

3. H2O2 production by mitochondria from females is significantly lower than from males

The importance of the rate of H2O2 production in determining life span has been highlighted by Barja [8]. The intramitochondrial steady-state concentrations of   and H2O2 are directly related to the rates of   and H2O2 production and inversely related to the enzymatic activity of manganese-superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx), which constitute the mitochondrial utilization pathways for   and H2O2. We measured the rate of H2O2 production in the presence of succinate or malate plus pyruvate. In both cases, mitochondria from females produced approximately half the amount of H2O2 than those from males. Mitochondrial H2O2, whose stoichiometric precursor is  , exerts a considerable part of the  toxicity through a Fe-catalysed Fenton chemistry [9], then, it is clear that the lower H2O2 production in females should be associated with a lower oxidative damage. In the following section, we describe the different oxidative damage in males and females [10] and [11].

4. Oxidative damage to key mitochondrial components is significantly higher in males than in females

Glutathione is a major intracellular antioxidant, whose concentration is similar to that of glucose [12] and in fact, it constitutes the major low molecular weight thiol in cells [13]. The levels of intracellular glutathione have been considered a biological marker of ageing [14]. We found that mitochondrial glutathione is related to the damage associated with ageing [15].

Table 1 shows that mitochondrial glutathione levels in males are approximately half than those found in females. DNA is a key component of the mitochondrial machinery [16]. We, and other groups, found that its degree of oxidation increases with ageing [7] and [17]. We have found (Table 1) that the levels of 8-oxo-deoxyguanosine (8-oxo-dG) (an excellent indicator of oxidative damage to DNA) are fourfold higher in males than in females [10]. This is the highest change we have observed in mitochondrial DNA oxidation in any physiological situation and shows that the chronic, continuous, increase in free radical production in males results in a marked oxidative and mutagenic lesion in mitochondrial DNA [18].

5. Females behave as double transgenics overexpressing mitochondrial superoxide dismutase and GPx

We searched for an explanation of the remarkable difference in free radical production between genders. Since the mitochondrial steady-state concentrations of   and H2O2 are defined by the ratio of the rates of production and utilization of these species, we determined the mitochondrial activity and expression of Mn-SOD and GPx [19]. Table 1 shows that the expression of Mn-SOD, i.e., the mitochondrial SOD isoenzyme, is approximately double in females than in males. Its activity follows a parallel pattern of change.

In a similar fashion, GPx expression and activity is markedly increased in females when compared with males. The fact that females have a higher GPx activity than males was already observed in the 1960s [20]but this was not then related to the different longevity between genders. A few years ago Orr and Sohal [21]observed that Drosophila that overexpress either SOD or catalase (they lack GPx) did not increase their average life span. However, when they overexpressed both, the life span was increased. We have found that females overexpress both superoxide dismutase and GPx (both of them mitochondrial enzymes, Table 1). Moreover, this increase can be attributed to oestrogens (see below).

6. Expression of 16S ribosomal RNA (16S rRNA) and glutathione levels, both biological markers of ageing, show that females are younger than males of the same chronological age

The search for reliable biomarkers of ageing is an important issue in gerontology. Hazelton and Lang [14] have shown that glutathione can be considered one such biomarker. A few years ago Marco and his group reported that 16S rRNA expression progressively decreases with ageing in Drosophila [22]. Moreover, in an independent study Davies and co-workers [23] reported that the same molecule, i.e., 16S rRNA decreases under conditions of oxidative stress.

Thus, we tested [10] the hypothesis that if females are biologically younger than males of the same chronological age, they ought to express more 16S rRNA than males. This is indeed the case and the expression of 16S rRNA is more than threefold higher in females than in males of the same age (Table 1).

7. Oestrogens do not act as chemical antioxidants in vivo: they exert their antioxidant effect by upregulation of the expression of antioxidant genes

Oestrogens are antioxidants in vitro [24]. However, at physiological concentration it is very unlikely that they may act as such, especially due to their low concentration in plasma. A simple calculation indicates that if the recommended dose of oestradiol in oestrogen replacement therapy is 50 μg/day and the recommended dose of vitamin E as supplement is 500 mg/day; oestrogen ought to be 10 000 times more potent than vitamin E to have a similar antioxidant capacity and this is obviously not the case. Yet biological experiments indicate that oestrogens have a powerful antioxidant effect in vivo: mitochondrial H2O2 production is significantly increased (by more than 50%) after ovariectomy and this is completely prevented when ovariectomised rats are treated with oestradiol at doses similar to those used in oestrogen replacement therapy (for details see [9]). We then tested if the antioxidant effect of oestradiol is exerted through the interaction of the hormone with the oestrogen receptors in MCF 7 cells, the human mammary cell line. When these cells were incubated with oestradiol, the rate of H2O2 production was significantly decreased. However, when the cells were co-incubated with oestradiol and tamoxifen (an oestrogen receptor modulator) the rate of H2O2 production was similar to controls. This indicates that the antioxidant effect of oestrogen is mediated by the interaction of oestradiol with the oestrogen receptor.

We next wanted to elucidate the mechanism by which oestradiol might act to increase the expression of mitochondrial antioxidant enzymes. A direct genomic effect of oestradiol was unlikely because neither superoxide dismutase nor GPx have oestrogen responsive elements in their promoter region. Thus, it was likely that the action of estradiol could be mediated via intracellular signalling cascades. We tested the effect of mitogen activated protein (MAP) kinases by using an inhibitor of the phosphorylation of these kinases, i.e., UO126. Our experiments show that UO126 completely inhibited the lowering effect of estradiol on the level of H2O2 in cells (Table 2).

 

Table 2.

Physiological concentrations of oestradiol decrease H2O2 levels in human MCF-7 cells mediated by estrogen receptors/MAPK/NF-κB signalling pathway

nmol H2O2/mg prot

Control

1.50 ± 0.55

Oestradiol 0.2 nM

0.66 ± 0.14**

Oestradiol 0.2 nM + tamoxifen 15 μM

1.72 ± 0.12

Oestradiol 0.2 nM + UO126 1 μM

1.06 ± 0.18

Oestradiol 0.2 nM + PDTC 200 μM

1.31 ± 0.15

Data are expressed as means ± S.D. for 8–10 different experiments. The statistical significance is expressed as ∗∗P < 0.01 vs. control.

[This explains why women who are chemical castrated or have an oophorectomy without subsequent estrogen die sooner than then on estradiol HRT—see Danish study]. 

 

MAP kinases are known to activate nuclear factor kappa B (NF-κB). Thus, we tested whether oestradiol acts by activating it. NF-κB would then be able to upregulate the expression of both SOD and GPx genes, whose promoters contain putative NF-κB-binding motifs. This is indeed the case: when cells were incubated with pyrrolidine dithiocarbamate (PDTC), an inhibitor of the IKB degradation, and therefore an inhibitor of the NF-κB translocation to the nucleus, the effect of oestradiol on the upregulation of antioxidant enzyme expression was prevented (Table 2). Using these pharmacological inhibitors of the signalling pathways, we demonstrate that oestradiol upregulates the expression of Mn-SOD and GPx mediated by the following pathway: interaction with membrane oestrogen receptor → activation of MAP kinases → activation of NF-κB → upregulation of gene expression (Table 2).

8. Phytoestrogens mimic the beneficial effects of oestrogens on the upregulation of antioxidant, longevity-related genes

The effect of oestradiol as an upregulator of antioxidant, longevity-related genes indicates that its administration might be beneficial to increase longevity, particularly of males, to reach a life span similar to females. However, considerable evidence has shown that oestrogen replacement therapy after menopause may have set backs [25]. Phytoestrogens constitute an interesting alternative. Their beneficial effects have been reported repeatedly [26] and, to our knowledge very few, if any, serious reports have shown detrimental effects. Thus, we tested the effect of 0.5 μM genistein, one of the major phytoestrogens in soya [27] on the H2O2 levels in MCF 7 cells. This can be considered as nutritionally relevant as it is the concentration normally found in the blood of people in the Far East who eat relatively large quantities of soya in their normal diet. This concentration is, however, significantly higher than the one found in people living in the Western world. We found that genistein significantly decreases H2O2 levels in cells and that, just as with oestradiol, this effect is mediated by oestrogen receptors.

We then studied if the signalling pathway that we had found to explain the antioxidant effects of oestradiol also acted for genistein and found that indeed this is the case and that genistein increases MAP kinases and activates NF-κB resulting in an upregulation of the antioxidant gene superoxide dismutase.

9. Concluding remarks

In a series of studies, we have attempted to elucidate the reasons for the different life span between males and females. In vivo experiments showed that oestrogens are responsible for the higher mitochondrial free radical production in males than in females.

Oestradiol does not act as a chemical antioxidant but rather it upregulates the expression of genes encoding for antioxidant enzymes such as Mn-SOD and GPx, both mitochondrial enzymes.

In vitro experiments (mainly using a human mammary gland cellular line) have shown that oestradiol acts through the interaction with oestrogen receptors. The cell-signalling pathway involved is oestrogen → binding to oestrogen receptor → MAPK phosphorylation → NF-κB activation → upregulation of antioxidant genes.Fig. 1 summarizes these findings.

Fig. 1. 

Proposed mechanism for the action of oestradiol on the expression of antioxidant, longevity-related genes.

Figure options

Phytoestrogens are an interesting alternative to oestradiol to decrease free radical production by mitochondria and, thus, to increase life span of males. We have recently shown that, at least, in vitro this is the case and that they bind to oestrogen receptors and activate the same signalling pathway as oestradiol does. The effect of dietary supplementation with phytoestrogens on longevity, particularly to elucidate if they can increase the life span of males to a similar longevity as that of females, remains to be studied in the near future.

The possible importance of these studies lies in the fact that half of the population (males) live ≈10% less than the other half (females). An understanding of the reasons for this difference of longevity may help us to increase the longevity of males and to understand the basic phenomenon of ageing, and to search for safe ways to increase life span of males.

Acknowledgements

Work reported from this laboratory was supported by CICYT (BFI-2001-2849 and SAF2004-03755 to J.V.), from CICYT (SAF2002/00885 to F.V.P.) and from Instituto de Salud Carlos III, RCMN (C03/08), Madrid, Spain. We are grateful to Dolores Royo for her skillful technical assistance.

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Corresponding author

 

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

http://en.wikipedia.org/wiki/Oophorectomy#Long-term_effects  http://en.wikipedia.org/wiki/Oophorectomy

 

Oophorectomy /ˌ.əfəˈrɛktəmi/ (from Greek ᾠοφόρος, ōophóros, "egg-bearing" + ἐκτομή, ektomḗ, "a cutting out of") is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term has been traditionally used in basic science research to describe the surgical removal of ovaries in laboratory animals. Removal of the ovaries in women is the biological equivalent of castration in males. [It is commonly done with a hysterectomy in women.  Doctors based on Pharma’s junk since often chemically castrate men and women with cancer of the breast, ovaries, uterus, or prostate.]

  

Oophorectomy has serious long-term consequences stemming mostly from the hormonal effects of the surgery and extending well beyond menopause. The reported risks and adverse effects include premature death,[10][11] cardiovascular disease, cognitive impairment or dementia,[12] parkinsonism,[13] osteoporosis and bone fractures, decline in psychological wellbeing,[14] and decline in sexual function. Hormone replacement therapy does not always reduce the adverse effects.[3]  Women younger than 45 who have had their ovaries removed face a mortality risk 170% higher than women who have retained their ovaries. Retaining the ovaries when a hysterectomy is performed is associated with better long-term survival.[10] Hormone therapy for women with oophorectomies performed before age 45 improves the long-term outcome and all-cause mortality rates.  When the ovaries are removed, a woman is at a seven times greater risk of cardiovascular disease.  The ovaries produce hormones a woman needs throughout her entire life, in the quantity they are needed, at the time they are needed in response to and as part of the complex endocrine system. Oophorectomy is associated with an increased risk of osteoporosis and bone fractures.  Reduced levels of testosterone in women is predictive of height loss, which may occur as a result of reduced bone density.[30] In women under the age of 50 who have undergone oophorectomy, hormone replacement therapy (HRT) is often used to offset the negative effects of sudden hormonal loss (for example early-onset osteoporosis) as well as menopausal problems like hot flushes (also called "hot flashes") that are usually more severe than those experienced by women undergoing natural menopause.   Oophorectomy substantially impairs sexuality.[31] Substantially more women who had both an oophorectomy and a hysterectomy reported libido loss, difficulty with sexual arousal, and vaginal dryness than those who had a less invasive procedure (either hysterectomy alone or an alternative procedure), and hormone replacement therapy was not found to improve these symptoms.  [This is because the current doses are too low, might not contain estradiol, and the progestin—depending on which one—blocks some of the benefits of estradiol.  For this reason I highly recommend natural HRT from a compounding pharmacy consisting of estradiol and progesterone, either pill or topical—see http://healthfully.org/rc/id2.html]. 

 

Non-hormonal treatments[edit]

The side effects of oophorectomy may be alleviated by medicines other than hormonal replacement. Non-hormonal biphosphonates (such as Fosamax and Actonel) increase bone strength and are available as once-a-week pills. Low-dose selective serotonin reuptake inhibitors (such as Paxil and Prozac) alleviate vasomotor menopausal symptoms, i.e. "hot flashes".   [Both choices are a hot dream of big pharma.  Biphosphonates are worse than nothing at all—see Worst Pill.  They go to the bone, increase bone density (surrogate outcome), but do not prevent bone fractures, and have major side effects. To give a downer such as Paxil, Prozac, or other SSRI is to cause cognitive impairment, addiction, and long-term psychiatric problems, especially depression.  Calling these drugs antidepressants, or other labels is pure marketing bull shit.] 

Hormonal treatments[edit]

In general, hormone replacement therapy is somewhat controversial due to the known carcinogenic and thrombogenic properties of estrogen; however, many physicians and patients feel the benefits outweigh the risks in women who may face serious health and quality of life issues as a consequence of early surgical menopause.The ovarian hormones estrogen, progesterone, and testosterone are involved in the regulation of hundreds of bodily functions; it is believed by some doctors that hormone therapy programs mitigate surgical menopause side effects such as increased risk of cardiovascular disease,[36] and female sexual dysfunction.[37] 

[Note the bad press concerning HRT is a result of 2-land-mark studies using Prempro, the worst formulation of HRT.  It contains mare estrogens and MPA which blocks several of the benefits of estrogen—see http://healthfully.org/rc/id2.html for an more complete critique.]  

The Leisure World (senior community) long-term population study of 8,801 women.  HRT was associated with reduced mortality, with the risk lowest for those taking HRT for 15 or more years.  The Leisure World Study is a population study, and thus isn’t controlled for confounding variables such as related to lifestyle, and health prior to commencing with HRT.  Moreover, the results for HRT has been diluted by the use of Prempro, both the most widely used and worst.  See HRT for an explanation of the reasons as to the inferiority of equine (horse) estrogen and the progestin MPA which blocks the cardio-protective effect of estrogen. 

Far superior results are to be had with the most potent form of human estrogen, estradiol.  The tricyclic Trisekvens; Novo Nordisk, Denmark in a randomized trial compared to a placebo.  The intervention was for 11 years.  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)”… on healthfully.org and BMJ 2012 at http://www.bmj.com/content/345/bmj.e6409?etoc

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A study that confirms the science support estradiol’s benefits

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373269/ Menopause. 2006 Jan-Feb; 13(1): 12–18.

doi:  10.1097/01.gme.0000172880.40831.3b

Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study

Annlia Paganini-Hill, PhD,1 Maria M. Corrada, ScD,2 and Claudia H. Kawas, MD3

Author information ► Copyright and License information ►

Abstract

Objective

To examine the effect of postmenopausal estrogen therapy (ET), including duration and recency of use, on all-cause mortality in older women.

Design

As part of a prospective cohort study of residents of a California retirement community begun in the early 1980s, Leisure World Cohort women (median age, 73 y) completed a postal health survey including details on ETuse and were followed up for 22 years (1981–2003). Age- and multivariate-adjusted risk ratios (RR) and 95% CIs were calculated using proportional hazard regression.

Results

Of the 8,801 women, 6,626 died during follow-up (median age, 88 y). ET users had an age-adjusted mortality rate of 52.9 per 1,000 person-years compared with 56.5 among lifetime nonusers (RR = 0.91; 95% CI, 0.87–0.96). Risk of death decreased with both increasing duration of ET and decreasing years since last use (P for trend <0.001). The risk was lowest among long-term (≥15 y) users (RR = 0.83; 95% CI, 0.74–0.93 for 15–19 y and RR = 0.87; 95% CI, 0.80–0.94 for 20+ y). For long-term users, the age-adjusted mortality rate was 50.4 per 1,000 person-years. Lower-dose users (≤0.625 mg) had a slightly better survival rate than higher-dose users (RR = 0.84; 95% CI, 0.78–0.91 vs RR = 0.91; 95% CI, 0.83–0.97). Risk did not differ by route of administration (P = 0.56). Further adjustment for potential confounders had little effect on the observed RRs for ET.

Conclusion

Long-term ET is associated with lower all-cause mortality in older women.

Keywords: Mortality, Longevity, Estrogen therapy, Risk factors

Full follows below at link https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373269/

 

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