Hormone replacement therapy enhances IGF‐1 signaling in skeletal muscle by diminishing miR‐182 and miR‐223 expressions: a study on postmenopausal monozygotic twin pairs

MiRNAs are fine‐tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co‐twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen‐based hormone replacement therapy (HRT) to explore estrogen‐dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62‐years‐old monozygotic female twin pairs discordant for HRT (median 7 years). MCF‐7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR‐182, miR‐223 and miR‐142‐3p expressions in HRT using than in their nonusing co‐twins. Insulin/IGF‐1 signaling emerged one common pathway targeted by these miRNAs. IGF‐1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR‐182 and miR‐223 on IGF‐1R and FOXO3A mRNA as well as a dose‐dependent miR‐182 and miR‐223 down‐regulations concomitantly with up‐regulation of FOXO3A and IGF‐1R expression. Novel finding is the postmenopausal HRT‐reduced miRs‐182, miR‐223 and miR‐142‐3p expression in female skeletal muscle. The observed miRNA‐mediated enhancement of the target genes' IGF‐1R and FOXO3A expression as well as the activation of insulin/IGF‐1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.     

Differential influence of peripheral and systemic sex steroids on skeletal muscle quality in pre- and postmenopausal women

Aging is associated with gradual decline of skeletal muscle strength and mass often leading to diminished muscle quality. This phenomenon is known as sarcopenia and affects about 30% of the over 60-year-old population. Androgens act as anabolic agents regulating muscle mass and improving muscle performance. The role of female sex steroids as well as the ability of skeletal muscle tissue to locally produce sex steroids has been less extensively studied. We show that despite the extensive systemic deficit of sex steroid hormones in postmenopausal compared to premenopausal women, the hormone content of skeletal muscle does not follow the same trend. In contrast to the systemic levels, muscle tissue of post- and premenopausal women had similar concentrations of dehydroepiandrosterone and androstenedione, while the concentrations of estradiol and testosterone were significantly higher in muscle of the postmenopausal women. The presence of steroidogenetic enzymes in muscle tissue indicates that the elevated postmenopausal steroid levels in skeletal muscle are because of local steroidogenesis. The circulating sex steroids were associated with better muscle quality while the muscle concentrations reflected the amount of infiltrated fat within muscle tissue. We conclude that systemically delivered and peripherally produced sex steroids have distinct roles in the regulation of neuromuscular characteristics during aging.     

Intramuscular sex steroid hormones are associated with skeletal muscle strength and power in women with different hormonal status

Estrogen (E₂)‐responsive peripheral tissues, such as skeletal muscle, may suffer from hormone deficiency after menopause potentially contributing to the aging of muscle. However, recently E₂ was shown to be synthesized by muscle and its systemic and intramuscular hormone levels are unequal. The objective of the study was to examine the association between intramuscular steroid hormones and muscle characteristics in premenopausal women (n = 8) and in postmenopausal monozygotic twin sister pairs (n = 16 co‐twins from eight pairs) discordant for the use of E₂‐based hormone replacement. Isometric skeletal muscle strength was assessed by measuring knee extension strength. Explosive lower body muscle power was assessed as vertical jump height. Due to sequential nature of enzymatic conversion of biologically inactive dehydroepiandrosterone (DHEA) to testosterone (T) and subsequently to E₂ or dihydrotestosterone (DHT), separate linear regression models were used to estimate the association of each hormone with muscle characteristics. Intramuscular E₂, T, DHT, and DHEA proved to be significant, independent predictors of strength and power explaining 59–64% of the variation in knee extension strength and 80–83% of the variation of vertical jumping height in women (P < 0.005 for all models). The models were adjusted for age, systemic E₂, and total body fat mass. The statistics used took into account the lack of statistical independence of twin sisters. Furthermore, muscle cells were shown to take up and actively synthesize hormones. Present study suggests intramuscular sex steroids to associate with strength and power regulation in female muscle providing novel insight to the field of muscle aging.     

Changes in intra-abdominal fat in early postmenopausal women: effects of hormone use

Objective: Intra‐abdominal fat (IAF) accumulates with age, is greater among postmenopausal vs. premenopausal women, and is linked to risk for both type 2 diabetes and cardiovascular disease. Whether hormone replacement therapy (HRT) prevents or attenuates changes in IAF and related risk factors is not clear. The objectives of this observational study were to 1) determine whether HRT attenuated the expected age‐related increase in IAF and 2) identify the independent effects of HRT and fat distribution on changes in disease risk factors. Research Methods and Procedures: Subjects were early postmenopausal white women 45 to 55 years of age. Women either used HRT at the time of enrollment (n = 33) or did not (n = 17). Subjects were evaluated at baseline and 2 years for body composition (DXA), body fat distribution (computed tomography), insulin sensitivity (Si; minimal model), and serum lipids. Results: IAF increased significantly over 2 years, and this increase was not attenuated by HRT. HRT users had less IAF throughout the study. HRT users showed an increase in Si, whereas non‐users showed a decrease. Superficial subcutaneous adipose tissue was significantly and independently related to total cholesterol, whereas IAF was related to high‐density lipoprotein cholesterol, triglycerides, and Si. Discussion: HRT users had less IAF at baseline and throughout the study. Whether HRT altered the relationship between total body fat and IAF or whether differences between groups existed before the study should be addressed through a randomized, interventional study design. HRT had a significant effect on Si; IAF and superficial subcutaneous adipose tissue were significant determinants of disease risk factors.     

Obesity and Sarcopenia after Menopause Are Reversed by Sex Hormone Replacement Therapy

Objective: Menopause is linked to an increase in fat mass and a decrease in lean mass exceeding age‐related changes, possibly related to reduced output of ovarian steroids. In this study we examined the effect of combined postmenopausal hormone replacement therapy (HRT) on the total and regional distribution of fat and lean body mass. Research Methods and Procedures: Sixteen healthy postmenopausal women (age: 55 ± 3 years) were studied in a placebo‐controlled, crossover study and were randomized to 17β estradiol plus cyclic norethisterone acetate (HRT) or placebo in two 12‐week periods separated by a 3‐month washout. Total and regional body composition was measured by DXA at baseline and in the 10th treatment week in both periods. Changes were compared by a paired Student's t test. Results: The change in body weight during HRT was equal to the change during placebo (?24.6 g vs. ?164 g, p = 0.42), but relative fat mass was significantly reduced (?0.5% vs. +1.24%, p < 0.01). During HRT, compared with during placebo, lean body mass increased (+347 g vs. ?996 g, p < 0.01) and total fat mass decreased (?400 g vs. +836 g, p = 0.06). Total bone mineral content increased (+28.9 g vs. ?4.4 g, p = 0.04) and abdominal fat decreased (?185 g vs. +253 g, p = 0.04) during HRT compared with placebo. Discussion: HRT is linked to the reversal of both menopause‐related obesity and loss of lean mass, without overall change in body weight. The increase in lean body mass during HRT is likely explained by muscle anabolism, which in turn, prevents disease in the elderly.     

Glycolytic fast‐twitch muscle fiber restoration counters adverse age‐related changes in body composition and metabolism

Aging is associated with the development of insulin resistance, increased adiposity, and accumulation of ectopic lipid deposits in tissues and organs. Starting in mid‐life there is a progressive decline in lean muscle mass associated with the preferential loss of glycolytic, fast‐twitch myofibers. However, it is not known to what extent muscle loss and metabolic dysfunction are causally related or whether they are independent epiphenomena of the aging process. Here, we utilized a skeletal‐muscle‐specific, conditional transgenic mouse expressing a constitutively active form of Akt1 to examine the consequences of glycolytic, fast‐twitch muscle growth in young vs. middle‐aged animals fed standard low‐fat chow diets. Activation of the Akt1 transgene led to selective skeletal muscle hypertrophy, reversing the loss of lean muscle mass observed upon aging. The Akt1‐mediated increase in muscle mass led to reductions in fat mass and hepatic steatosis in older animals, and corrected age‐associated impairments in glucose metabolism. These results indicate that the loss of lean muscle mass is a significant contributor to the development of age‐related metabolic dysfunction and that interventions that preserve or restore fast/glycolytic muscle may delay the onset of metabolic disease.     

Hormone replacement therapy increases renal kallikrein excretion in healthy postmenopausal women

Hypertension and its related increase in cardiovascular morbidity in postmenopausal women is a major public health problem. The hypotensive property of urinary kallikrein has been described since 1909. Despite the controversy surrounding the effects of hormone replacement therapy on blood pressure regulation, its mechanisms remain incompletely understood, and no evidence has yet been provided for its effects on renal kallikrein excretion in postmenopausal women. In a double-blind, randomized study we examined the effects of hormone replacement therapy in the form of 2 mg 17-beta estradiol (ERT) or 2 mg 17-beta estradiol combined with continuous 5 mg medroxyprogesterone acetate (HRT) on urinary kallikrein excretion in postmenopausal women. Thirty-nine postmenopausal women collected their urine for 24 hours on two separate occasions 3 months apart. During the 3 month period women were randomized to placebo, ERT, or HRT. Urine samples were assayed for kallikrein activity, normalized to urine creatinine and expressed as mU/gm creatinine. Urinary kallikrein excretion increased significantly after 3 months in the ERT (p < 0.001) and HRT (p < 0.01) groups, and decreased non-significantly in the placebo group (p > 0.06). There were no significant blood pressure changes after 3 months of therapy. The findings demonstrate that hormone replacement therapy in the form of estrogen or estrogen combined with continuous medroxyprogesterone is effective in increasing urinary kallikrein excretion. Given that a decrease in kallikrein excretion may mark risk for development of hypertension, the findings of this study are of value in demonstrating a novel mechanism underlying cardioprotective properties of postmenopausal hormone replacement therapy in women without pre-existing coronary disease.     

Endothelium‐specific CYP2J2 overexpression attenuates age‐related insulin resistance

Ample evidences demonstrate that cytochrome P450 epoxygenase‐derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti‐inflammatory, and cardiovascular protective effects. In this study, we investigated the effects of endothelium‐specific CYP2J2 overexpression on age‐related insulin resistance and metabolic dysfunction. Endothelium‐specific targeting of the human CYP epoxygenase, CYP2J2, transgenic mice (Tie2‐CYP2J2‐Tr mice) was utilized. The effects of endothelium‐specific CYP2J2 overexpression on aging‐associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2‐CYP2J2‐Tr mice. Decreased insulin sensitivity and attenuated insulin signaling in aged skeletal muscle, adipose tissue, and liver were observed in aged adult male mice, and moreover, these effects were partly inhibited in 16‐month‐old CYP2J2‐Tr mice. In addition, CYP2J2 overexpression‐mediated insulin sensitization in aged mice was associated with the amelioration of inflammatory state. Notably, the aging‐associated increases in fat mass and adipocyte size were only observed in 16‐month‐old wild‐type mice, and CYP2J2 overexpression markedly prevented the increase in fat mass and adipocyte size in aged Tie2‐CYP2J2‐Tr mice, which was associated with increased energy expenditure and decreased lipogenic genes expression. Furthermore, these antiaging phenotypes of Tie2‐CYP2J2‐Tr mice were also associated with increased muscle blood flow, enhanced active‐phase locomotor activity, and improved mitochondrial dysfunction in skeletal muscle. Collectively, our findings indicated that endothelium‐specific CYP2J2 overexpression alleviated age‐related insulin resistance and metabolic dysfunction, which highlighted CYP epoxygenase‐EET system as a potential target for combating aging‐related metabolic disorders.     

17‐β estradiol attenuates the pro‐oxidant activity of corticotropin‐releasing hormone in macroendothelial cells

Corticotropin‐releasing hormone, which is the predominant regulator of neuroendocrine responses to stress, attenuates inflammation through stimulation of glucocorticoid release. Enhanced corticotropin‐releasing hormone expression has been detected in inflammatory cells of the vascular endothelium, where it acts as a local regulator of endothelial redox homeostasis. Estrogens have beneficial effects on endothelial integrity and function, though the mechanism underlying their antioxidative effect remains as yet largely unknown. We therefore investigated the effect of 17β‐estradiol on pro‐oxidant action of corticotropin‐releasing hormone in vitro in macroendothelial cells, and, more specifically, the role of 17β‐estradiol on corticotropin‐releasing hormone‐induced activities/release of the antioxidant enzymes namely, endothelial nitric oxide synthase, superoxide dismutase, catalase, and glutathione. We observed that 17β‐estradiol abolished the stimulatory effect of corticotropin‐releasing hormone on intracellular reactive oxygen species levels and counteracted its inhibitory effect on endothelial nitric oxide synthase activity and nitric oxide release. In addition, 17β‐estradiol significantly induced superoxide dismutase and catalase activity, an effect that was not significantly influenced by corticotropin‐releasing hormone. Finally, 17β‐estradiol significantly increased glutathione levels and the glutathione/glutathione + glutathione disulfide ratio, an action that was partially blocked by corticotropin‐releasing hormone. Our results reveal that 17β‐estradiol counterbalances corticotropin‐releasing hormone‐mediated pro‐inflammatory action and thereby maintains the physiological threshold of the endothelial cell redox environment. These observations may be of importance, considering the protective role of estrogen in the development of atherosclerosis.     

Does skeletal muscle have an ‘epi’‐memory? The role of epigenetics in nutritional programming,metabolic disease,aging and exercise

Skeletal muscle mass, quality and adaptability are fundamental in promoting muscle performance, maintaining metabolic function and supporting longevity and healthspan. Skeletal muscle is programmable and can ‘remember’ early‐life metabolic stimuli affecting its function in adult life. In this review, the authors pose the question as to whether skeletal muscle has an ‘epi’‐memory? Following an initial encounter with an environmental stimulus, we discuss the underlying molecular and epigenetic mechanisms enabling skeletal muscle to adapt, should it re‐encounter the stimulus in later life. We also define skeletal muscle memory and outline the scientific literature contributing to this field. Furthermore, we review the evidence for early‐life nutrient stress and low birth weight in animals and human cohort studies, respectively, and discuss the underlying molecular mechanisms culminating in skeletal muscle dysfunction, metabolic disease and loss of skeletal muscle mass across the lifespan. We also summarize and discuss studies that isolate muscle stem cells from different environmental niches in vivo (physically active, diabetic, cachectic, aged) and how they reportedly remember this environment once isolated in vitro. Finally, we will outline the molecular and epigenetic mechanisms underlying skeletal muscle memory and review the epigenetic regulation of exercise‐induced skeletal muscle adaptation, highlighting exercise interventions as suitable models to investigate skeletal muscle memory in humans. We believe that understanding the ‘epi’‐memory of skeletal muscle will enable the next generation of targeted therapies to promote muscle growth and reduce muscle loss to enable healthy aging.     

Aging impacts CD103+CD8+ T cell presence and induction by dendritic cells in the genital tract

As women age, susceptibility to systemic and genital infections increases. Tissue‐resident memory T cells (TRMs) are CD103⁺CD8⁺ long‐lived lymphocytes that provide critical mucosal immune protection. Mucosal dendritic cells (DCs) are known to induce CD103 expression on CD8⁺ T cells. While CD103⁺CD8⁺ T cells are found throughout the female reproductive tract (FRT), the extent to which aging impacts their presence and induction by DCs remains unknown. Using hysterectomy tissues, we found that endometrial CD103⁺CD8⁺ T cells were increased in postmenopausal compared to premenopausal women. Endometrial DCs from postmenopausal women were significantly more effective at inducing CD103 expression on allogeneic naïve CD8⁺ T cells than DCs from premenopausal women; CD103 upregulation was mediated through membrane‐bound TGFβ signaling. In contrast, cervical CD103⁺ T cells and DC numbers declined in postmenopausal women with age. Decreases in DCs correlated with decreased CD103⁺ T cells in endocervix, but not ectocervix. Our findings demonstrate a previously unrecognized compartmentalization of TRMs in the FRT of postmenopausal women, with loss of TRMs and DCs in the cervix with aging, and increased TRMs and DC induction capacity in the endometrium. These findings are relevant to understanding immune protection in the FRT and to the design of vaccines for women of all ages.     

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Sarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.     

Role of ovarian hormones in the regulation of protein metabolism in women: effects of menopausal status and hormone replacement therapy

The age-related decline in fat-free mass is accelerated in women after menopause, implying that ovarian hormone deficiency may have catabolic effects on lean tissue. Because fat-free tissue mass is largely determined by its protein content, alterations in ovarian hormones would likely exert regulatory control through effects on protein balance. To address the hypothesis that ovarian hormones regulate protein metabolism, we examined the effect of menopausal status and hormone replacement therapy (HRT) on protein turnover. Whole body protein breakdown, oxidation, and synthesis were measured under postabsorptive conditions using [(13)C]leucine in healthy premenopausal (n = 15, 49 +/- 1 yr) and postmenopausal (n = 18, 53 +/- 1 yr) women. In postmenopausal women, whole body protein turnover and plasma albumin synthesis rates (assessed using [(13)C]leucine and [(2)H]phenylalanine) were also measured following 2 mo of treatment with oral HRT (0.625 mg conjugated estrogens + 2.5 mg medroxyprogesterone acetate, n = 9) or placebo (n = 9). No differences in whole body protein breakdown, oxidation, or synthesis were found between premenopausal and postmenopausal women. Protein metabolism remained similar between groups after statistical adjustment for differences in adiposity and when subgroups of women matched for percent body fat were compared. In postmenopausal women, no effect of HRT was found on whole body protein breakdown, synthesis, or oxidation. In contrast, our results support a stimulatory effect of HRT on albumin fractional synthesis rate, although this did not translate into alterations in circulating albumin concentrations. In conclusion, our results suggest no detrimental effect of ovarian hormone deficiency coincident with the postmenopausal state, and no salutary effect of hormone repletion with HRT, on rates of whole body protein turnover, although oral HRT regimens may increase the synthesis rates of albumin.     

Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction

Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age‐related renal fibrosis are not elucidated. Herein, we found that Wnt/β‐catenin signaling and renin–angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β‐catenin activity, abolished renal fibrosis in d ‐galactose (d ‐gal)‐induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria‐targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC‐8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d ‐gal triggered the transduction of Wnt/β‐catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC‐8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β‐catenin signaling and the RAS could slow the onset of age‐related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction.     

Longitudinal associations of the endocrine environment on fat partitioning in postmenopausal women

Among postmenopausal women, declining estrogen may facilitate fat partitioning from the periphery to the intra-abdominal space. Furthermore, it has been suggested that excess androgens contribute to a central fat distribution pattern in women. The objective of this longitudinal study was to identify independent associations of the hormone milieu with fat distribution in postmenopausal women. Fifty-three healthy postmenopausal women, either using or not using hormone replacement therapy (HRT) were evaluated at baseline and 2 years. The main outcomes were intra-abdominal adipose tissue (IAAT), subcutaneous abdominal adipose tissue, and total thigh fat analyzed by computed tomography scanning and leg fat and total body fat mass measured by dual-energy X-ray absorptiometry. Serum estradiol, estrone, estrone sulfate, total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate), sex hormone-binding globulin (SHBG), and cortisol were assessed. On average, in all women combined, IAAT increased by 10% (10.5 cm(2)) over 2 years (P < 0.05). Among HRT users, estradiol was inversely associated with, and estrone was positively associated with, 2-year gain in IAAT. Among HRT nonusers, free testosterone was inversely associated with, and SHBG was positively associated with, 2-year gain in IAAT. These results suggest that in postmenopausal women using HRT, greater circulating estradiol may play an integral role in limiting lipid deposition to the intra-abdominal cavity, a depot associated with metabolically detrimental attributes. However, a high proportion of weak estrogens may promote fat partitioning to the intra-abdominal cavity over time. Furthermore, among postmenopausal women not using HRT, greater circulating free testosterone may limit IAAT accrual.     

The effects of postmenopausal hormone replacement therapy and oral contraceptives on the endogenous estradiol metabolism.

The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16alpha-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism--they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.     

The effects of estrogen on indices of skeletal muscle tissue damage after eccentric exercise in postmenopausal women

This study examined if estrogen (E) usage (in the form of hormone replacement therapy [HRT]) has a protective effect on skeletal muscle damage in postmenopausal women. Nine postmenopausal women (age 55.2 +/- 9.9 [mean +/- SD]) performed two exercise sessions at 70% of their maximal heart rate on HRT (E-HI) and without HRT (E-LO; following a 28-45 day HRT washout). All subjects followed a condition order of E-HI then E-LO with at least 42 days between exercise sessions. Serum creatine kinase (CK), perceived delayed onset muscle soreness (DOMS), and maximal quadriceps isometric force (MIF) were taken pre-exercise, 24, 48 and 72-hr post exercise. E-HI and E-LO conditions produced a rise in CK (p < 0.001) after exercise; but CK after E-HI was greater than in E-LO (p < 0.001) at 24 hours and at 48 hours. DOMS was significantly elevated at 24, 48, and 72-hr post each exercise session (p < 0.05). The greatest peak DOMS score occurred during the E-HI condition. MIF was similarly reduced after each exercise session (p < 0.05). These results suggest elevated E does not offer a protective effect to skeletal muscle; however, design limitations (i.e., condition order) confound the present data. Interestingly, an association between peak-CK during the E-LO condition and the number of washout days (r = +0.707, p < 0.05) between conditions existed. This suggests a longer washout period may be necessary to elucidate the actual E effects on skeletal muscle. These findings suggest that more work correcting for the present design limitations is warranted on this topic.