Effects Of Estrogen Replacement Research Articles

Protocol for a randomised, placebo-controlled, double-blinded clinical trial on the effect of oestrogen replacement on physical performance to muscle resistance exercise for older women with osteoarthritis of knee joint: the EPOK trial

BackgroundKnee osteoarthritis (KOA) is highly prevalent in older women, and previous studies suggest the involvement of hormonal factors play a role in the pathogenesis of osteoarthritis. KOA causes musculoskeletal impairment, resulting in decreased physical activity, muscle mass, and strength, which leads to sarcopenia and further increases the burden on healthcare systems. Oestrogen replacement therapy (ERT) improves joint pain and muscle performance in early menopausal women. Muscle resistance exercise (MRE) is a non-pharmacological method that preserves the physical functions of patients with KOA. However, data on short-term oestrogen administration combined with MRE in postmenopausal women, especially in those aged > 65 years, are limited. Therefore, this study presents a protocol of a trial aimed to examine the synergistic effect of ERT and MRE on lower-limb physical performance in older women with KOA.MethodsWe will conduct a double-blinded, randomised placebo-controlled trial in 80 Japanese women aged > 65 years living independently with knee pain. The participants will be randomly categorised into two groups: (1) 12-week MRE programme with transdermal oestrogen gel containing 0.54 mg oestradiol per push and (2) 12-week MRE programme with placebo gel. The primary outcome measured using the 30-s chair stand test, and secondary outcomes (body composition, lower-limb muscle strength, physical performance, self-reported measure of knee pain, and quality of life) will be measured at baseline, 3 months, and 12 months, and these outcomes will be analysed based on the intention-to-treat.DiscussionThe EPOK trial is the first study to focus on the efficacy of ERT on MRE among women aged > 65 years with KOA. This trial will provide an effective MRE to prevent KOA-induced lower-limb muscle weakness, confirming the benefit of short-term oestrogen administration.Trial registrationJapan Registry of Clinical Trials: jRCTs061210062. Registered 17th December 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs061210062.

MECHANISMS IN ENDOCRINOLOGY: Paracrine and endocrine control of the growth hormone axis by estrogen.

There is a strong biological link between the growth hormone (GH) and gonadal systems in growth, development and metabolism; however, regulatory interactions are poorly understood. Advances in estrogen biology and endocrine physiology have provided insights into mechanistic links between the two systems. Estrogens are synthesized from androgens by aromatase which is widely distributed in extragonadal tissues. Local generation of estrogens raise the possibility of paracrine control as an additional level to classical endocrine regulation of the GH system. To explore the mechanistic links, we review the pharmacology of estrogen, the effects of estrogen replacement, antagonism, and the impact of aromatase inhibition on the GH system as well as the metabolic sequelae. In men, estrogens derived from androgens drive the central secretion of GH, independent of the androgen receptor. In hypogonadal women, physiological replacement via a parenteral route evokes no effect while estrogen receptor antagonism and estrogen deprivation induce disparate effects, providing no consistent evidence that estrogens regulate the central secretion of GH via paracrine or endocrine mechanisms. However, delivery of estrogen by the oral route inhibits hepatic IGF-1 production, in turn increasing GH secretion via reduced feedback inhibition. This endocrine route-dependent effect of oral estrogen compounds on hepatic function induces detrimental metabolic effects on hypogonadal women. In conclusion, estrogens regulate the secretion and action of GH via complex paracrine and endocrine interactions and impart metabolic effects in a route- and gender-dependent manner. The metabolic sequelae of compounds mimicking, antagonizing, or depleting estrogens, should be considered in tailoring and optimizing their use.

Effects of estrogen replacement on bone geometry and microarchitecture in adolescent and young adult oligoamenorrheic athletes: A randomized trial

Effects of estrogen replacement on bone geometry and microarchitecture in adolescent and young adult oligoamenorrheic athletes: A randomized trial

Effects of Estrogen Replacement on Bone Geometry and Microarchitecture in Adolescent and Young Adult Oligoamenorrheic Athletes: A Randomized Trial.

Oligoamenorrheic athletes (OAs) have lower bone mineral density (BMD) and greater impairment of bone microarchitecture, and therefore higher fracture rates compared to eumenorrheic athletes. Although improvements in areal BMD (aBMD; measured by dual-energy X-ray absorptiometry) in OAs have been demonstrated with transdermal estrogen treatment, effects of such treatment on bone microarchitecture are unknown. Here we explore effects of transdermal versus oral estrogen versus no estrogen on bone microarchitecture in OA. Seventy-five OAs (ages 14 to 25 years) were randomized to (i) a 100-μg 17β-estradiol transdermal patch (PATCH) administered continuously with 200 mg cyclic oral micronized progesterone; (ii) a combined 30 μg ethinyl estradiol and 0.15 mg desogestrel pill (PILL); or (iii) no estrogen/progesterone (NONE) and were followed for 12 months. Calcium (≥1200 mg) and vitamin D (800 IU) supplements were provided to all. Bone microarchitecture was assessed using high-resolution peripheral quantitative CT at the distal tibia and radius at baseline and 1 year. At baseline, randomization groups did not differ by age, body mass index, percent body fat, duration of amenorrhea, vitamin D levels, BMD, or bone microarchitecture measurements. After 1 year of treatment, at the distal tibia there were significantly greater increases in total and trabecular volumetric BMD (vBMD), cortical area and thickness, and trabecular number in the PATCH versus PILL groups. Trabecular area decreased significantly in the PATCH group versus the PILL and NONE groups. Less robust differences between groups were seen at the distal radius, where percent change in cortical area and thickness was significantly greater in the PATCH versus PILL and NONE groups, and changes in cortical vBMD were significantly greater in the PATCH versus PILL groups. In conclusion, in young OAs, bone structural parameters show greater improvement after 1 year of treatment with transdermal 17β-estradiol versus ethinyl estradiol-containing pills, particularly at the tibia. © 2019 American Society for Bone and Mineral Research.

Effects of Estrogen Replacement on ACh‐Induced Relaxation in Mesenteric Arteries of Prediabetic Ovariectomized Rats

The risk of cardiovascular diseases (CVD) is lower in premenopausal women than in men, and this lower risk is related to the presumptive cardioprotective effects of female sex hormones, estrogen in particular. However, premenopausal women with diabetes not only lose this protection, they also experience a higher relative risk of CVD compared to diabetic men. Several lines of evidence suggest that endothelial dysfunction represents early steps in the development of vascular complications in diabetes, and hyperglycemia is the central initiating factor for those complications. Nonetheless, there is insufficient evidence to establish the timeline of the loss of this female‐specific protection in premenopausal patients with diabetes. The objective of this study was to investigate the effects of 17β‐estradiol (E2) on mesenteric arterial function in UC Davis type 2 diabetes mellitus (UCD‐T2DM) rats at the prediabetic stage.Mesenteric arteries (MA) were obtained from four groups of ovariectomized (ovex) female rats implanted with a subcutaneous pellet for 45 days: (1) Control, ovex + placebo, (2) Control, ovex + E2 (1.5mg/pellet), (3) prediabetic, ovex + placebo, (4) prediabetic, ovex + E2 (1.5mg/pellet). Endothelium‐dependent vasodilation (EDV) to acetylcholine (ACh, 10−8 to 10−5 M) in phenylephrine pre‐contracted mesenteric arterial rings were measured before and after indomethacin (Indo, 10μm), a cyclooxygenase (COX) inhibitor, followed by addition of L‐NAME (200μM), a nitric oxide synthase (NOS) inhibitor. When Indo and L‐NAME are administrated, the remaining EDV to ACh is referred to as the endothelium‐dependent hyperpolarization factor (EDHF)‐type relaxation.There were no significant differences in ACh‐ induced relaxation between placebo and E2 treated controls. However, the ACh responses in MA was markedly reduced in prediabetic treated with placebo. Treatment of prediabetic with E2 enhanced the ACh‐induced relaxation compared with its respective placebo group. Blocking of both COX and NOS completely abolished the relaxation responses to ACh in prediabetic, regardless of E2 replacement, suggesting no contribution of EDHF‐type relaxation in this group. The E2 replacement, however, increased the contribution of NO‐mediated vasodilation in MA of prediabetic rats. When compared with prediabetic groups, the effect of L‐NAME was much smaller in controls, specifically after E2 replacement, indicating an elevated contribution of EDHF‐type relaxation in E2‐treated control.These data show that EDV was impaired in ovex rats at prediabetic stage, possibly due to loss of EDHF. However, an intriguing observation of this study was that, at the pre‐diabetic stage, estrogen treated ovex rats exhibited intact EDV, regardless of loss of EDHF. This may be due to elevated contribution of NO to EDV in this group. Additional studies are required to establish the role of estrogen replacement in diabetic stages.Support or Funding InformationSupported by NHLBIThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Prospective, randomized, double-blind, placebo-controlled phase IIa clinical trial on the effects of an estrogen-progestin combination as add-on to inpatient psychotherapy in adult female patients suffering from anorexia nervosa

BackgroundThere is a need for novel treatment approaches in anorexia nervosa (AN). While there is broad knowledge with regard to altered appetite regulation and neuropsychological deficits in AN patients on the one hand, and the effects of estrogen replacement upon neuropsychological performance in healthy subjects on the other, up to now, no study has implemented estrogen replacement in AN patients, in order to examine its effects upon AN-associated and general psychopathology, neuropsychological performance and concentrations of peptide components of the hypothalamus-pituitary-adrenal (HPA) axis and within appetite-regulating circuits.MethodsThis is a randomized placebo-controlled clinical trial on the effects of a 10-week oral estrogen replacement (combination of ethinyl estradiol 0.03 mg and dienogest 2 mg) in adult female AN patients. The primary target is the assessment of the impact of sex hormone replacement upon neuropsychological performance by means of a neuropsychological test battery consisting of a test for verbal intelligence, the Trail making test A and B, a Go/No-go paradigm with food cues and the Wisconsin Card Sorting Test. Secondary targets include a) the examination of safety and tolerability (as mirrored by the number of adverse events), b) assessments of the impact upon eating disorder-specific psychopathology by means of the Eating Disorder Examination Questionnaire (EDE-Q) and the Eating Disorder Inventory-2 (EDI-2), c) the influence upon anxiety using the State-Trait-Anxiety Inventory (STAI), d) assessments of plasma cortisol levels during a dexamethasone-suppression test and appetite-regulating plasma peptides (ghrelin, leptin, insulin, glucose) during an oral glucose tolerance test and, e) a possible impact upon the prescription of antidepressants.DiscussionThis is the first study of its kind. There are no evidence-based psychopharmacological options for the treatment of AN. Thus, the results of this clinical trial may have a relevant impact on future treatment regimens. Novel approaches are necessary to improve rates of AN symptom remission and increase the rapidity of treatment response. Identifying the underlying biological (e.g. neuroendocrinological) factors that maintain AN or may predict patient treatment response represent critical future research directions. Continued efforts to incorporate novel pharmacological aspects into treatments will increase access to evidence-based care and help reduce the burden of AN.Trial registrationEuropean Clinical Trials Database, EudraCT number 2015–004184-36, registered November 2015; ClinicalTrials.gov Identifier: NCT03172533, retrospectively registered May 2017.

Effects of estrogen replacement on stress-induced cardiovascular responses via renin-angiotensin system in ovariectomized rats

The purpose of this study was to determine whether chronic estrogen replacement in ovariectomized rats inhibits the pressor response to psychological stress by attenuating the activation of the renin-angiotensin system. Female Wistar rats aged 9 wk were ovariectomized. After 4 wk, the rats were randomly assigned to be implanted subcutaneously with pellets containing either 17β-estradiol (E2) or placebo (Pla). After 4 wk of treatment, the rats underwent cage-switch stress and, in a separate experiment, a subset received an infusion of angiotensin II. The cage-switch stress rapidly elevated blood pressure (BP) and heart rate (HR) as measured by radiotelemetry in both groups. However, the BP and HR responses to the stress were significantly attenuated in the E2 group compared with the Pla group. An angiotensin II type 1 receptor blocker, losartan, given in drinking water, abolished the difference in the pressor response to stress between the two groups. Moreover, the stress-induced elevation in plasma renin activity and angiotensin II concentration was significant in the Pla group, but not in the E2 group. In addition, the expression of renin mRNA in the kidney was lower in the E2 group relative to the Pla group. Finally, we found that intravenous angiotensin II infusion increased BP and decreased HR to a similar degree in both groups. These results suggest that the inhibitory effects of estrogen on psychological stress-induced activation of the renin-angiotensin system could be at least partially responsible for the suppression of the pressor responses to psychological stress seen in estrogen-replaced ovariectomized rats.

Combined Effect of Estrogen Replacement and Angiotensin II Type I Receptor Blocker on Endothelial Dysfunction and Oxidative Stress in Ovariectomized Rats

Combined Effect of Estrogen Replacement and Angiotensin II Type I Receptor Blocker on Endothelial Dysfunction and Oxidative Stress in Ovariectomized Rats

Impact of Physiologic Estrogen Replacement on Anxiety Symptoms, Body Shape Perception, and Eating Attitudes in Adolescent Girls With Anorexia Nervosa

Anorexia nervosa is characterized by low weight, aberrant eating attitudes, body image distortion, and hypogonadism. Anxiety is a common comorbid condition. Estrogen replacement reduces anxiety in animal models, and reported variations in food intake across the menstrual cycle may be related to gonadal steroid levels. The impact of estrogen replacement on anxiety, eating attitudes, and body image has not been reported in anorexia nervosa. We hypothesized that physiologic estrogen replacement would ameliorate anxiety and improve eating attitudes without affecting body image in anorexia nervosa. Girls 13-18 years old with anorexia nervosa (DSM-IV) were randomized to transdermal estradiol (100 μg twice weekly) with cyclic progesterone or placebo patches and pills for 18-months, between 2002 and 2010. The State-Trait Anxiety Inventory for Children (STAIC), the Eating Disorders Inventory-2 (EDI-2), and the Body Shape Questionnaire (BSQ-34) were administered. 72 girls completed these measures at baseline (n=38 [girls receiving estrogen] and n=34 [girls receiving placebo]) and 37 at 18 months (n=20 [girls receiving estrogen] and n=17 [girls receiving placebo]). The primary outcome measure was the change in these scores over 18 months. Estrogen replacement caused a decrease in STAIC-trait scores (-3.05 [1.22] vs. 2.07 [1.73], P=.02), without impacting STAIC-state scores (-1.11 [2.17] vs. 0.20 [1.42], P=.64). There was no effect of estrogen replacement on EDI-2 or BSQ-34 scores. Body mass index (BMI) changes did not differ between groups, and effects of estrogen replacement on STAIC-trait scores persisted after controlling for BMI changes (P=.03). Increases in serum estradiol were significantly associated with decreases in STAIC-trait scores (Spearman ρ = -0.45, P=.03). Estrogen replacement improved trait anxiety (the tendency to experience anxiety) but did not impact eating attitudes or body shape perception. ClinicalTrials.gov identifier: NCT00088153.

Effects of Estrogen Replacement and Lower Androgen Status on Skeletal Muscle Collagen and Myofibrillar Protein Synthesis in Postmenopausal Women

Our aim was to determine synthesis rate of myofibrillar and collagen proteins in 20 postmenopausal women, who were either nonusers (Controls) or users of estrogen replacement therapy (ERT) after hysterectomy/oophorectomy. Myofibrillar and muscle collagen protein fractional synthesis rate (FSR) were determined in a nonexercised leg and 24 hours after exercise in the contralateral leg. A significant interaction between treatment and mechanical loading was observed in myofibrillar protein FSR. At rest, myofibrillar protein FSR was found to be lower in ERT users than in Controls. Exercise enhanced myofibrillar protein FSR only in ERT users. Similarly, muscle collagen FSR tended to be lower in ERT users compared with Controls. In ERT participants, the androgen profile was reduced, whereas estradiol and sex hormone-binding globulin were higher. In conclusion, at rest, myofibrillar protein FSR was lower in hysterectomized/oophorectomized women using ERT compared with healthy postmenopausal women. Nevertheless, resistance exercise in combination with ERT seems to have a counteracting effect on myofibrillar FSR in hysterectomized/oophorectomized women.

Estrogen Reduces Aldosterone, Upregulates Adrenal Angiotensin II AT2 Receptors and Normalizes Adrenomedullary Fra-2 in Ovariectomized Rats

We studied the effect of ovariectomy and estrogen replacement on expression of adrenal angiotensin II AT₁ and AT₂ receptors, aldosterone content, catecholamine synthesis, and the transcription factor Fos-related antigen 2 (Fra-2). Ovariectomy increased AT₁ receptor expression in the adrenal zona glomerulosa and medulla, and decreased adrenomedullary catecholamine content and Fra-2 expression when compared to intact female rats. In the zona glomerulosa, estrogen replacement normalized AT₁ receptor expression, decreased AT_1B receptor mRNA, and increased AT₂ receptor expression and mRNA. Estrogen treatment decreased adrenal aldosterone content. In the adrenal medulla, the effects of estrogen replacement were: normalized AT₁ receptor expression, increased AT₂ receptor expression, AT₂ receptor mRNA, and tyrosine hydroxylase mRNA, and normalized Fra-2 expression and catecholamine content. We demonstrate that the constitutive adrenal expression of AT₁ receptors, catecholamine synthesis and Fra-2 expression are partially under the control of reproductive hormones. Our results suggest that estrogen treatment decreases aldosterone production through AT₁ receptor downregulation and AT₂ receptor upregulation. AT₂ receptor upregulation and modulation of Fra-2 expression may participate in the estrogen-dependent normalization of adrenomedullary catecholamine synthesis in ovariectomized rats. The AT₂ receptor upregulation and the decrease in AT₁ receptor function and in the production of the fluid-retentive, pro-inflammatory hormone aldosterone partially explain the protective effects of estrogen therapy.

Effects of Estrogen Replacement on Skeletal Muscle of Aged Mice that Experienced Natural Ovarian-Failure

Effects of Estrogen Replacement on Skeletal Muscle of Aged Mice that Experienced Natural Ovarian-Failure

Effects of estrogen replacement on oxidative stress induced by psychological stress in ovariectomized rats

Effects of estrogen replacement on oxidative stress induced by psychological stress in ovariectomized rats

Effects of estrogen replacement with and without medroxyprogesterone acetate on brachial flow-mediated vasodilator responses in postmenopausal women with coronary artery disease

Hormone therapy has been shown to have no cardioprotective effect and may, in fact, be harmful in older postmenopausal women. Estrogen has been shown to enhance endothelial-dependent flow-mediated vasodilation (FMD) in healthy and younger women. The effect of estrogen on older and less healthy postmenopausal women with atherosclerosis is unclear. The Estrogen Replacement and Atherosclerosis trial randomized 309 postmenopausal women with established coronary atherosclerosis (mean, 65.8 years) to unopposed estrogen (conjugated estrogen, 0.625 mg), estrogen plus 2.5 mg medroxyprogesterone actate (MPA), or placebo. After mean of 3.2 years of follow-up, brachial FMD was measured using 2-dimensional ultrasound in women available for follow-up at 4 of the 5 clinic sites (n = 198). The %FMD of the brachial artery was not statistically different in the placebo arm compared with either unopposed estrogen or estrogen + MPA arm in both the adjusted and the unadjusted models. Subsequent analysis combining the estrogen arm with the estrogen + MPA arm and comparing with the placebo arm was also not significant in both the adjusted and the unadjusted models. Similar results were obtained when analyses were limited to women who took >80% of the study medication over the course of the trial (n = 133). An average of 3.2 years of treatment with unopposed estrogen or estrogen plus progestins did not result in significant improvements in endothelial vasodilation compared with placebo. This apparent absence of an effect on brachial artery endothelial function in older postmenopausal women with established coronary heart disease may help explain the lack of benefit of estrogen for secondary prevention of coronary heart disease.

Effect of estrogen replacement on body fluid and blood pressure regulation in ovariectomized rats.

Effect of estrogen replacement on body fluid and blood pressure regulation in ovariectomized rats.

Effects of Estrogen Replacement on Physical Activity and Body Mass in Aged Mice That Have Experienced Natural Ovarian Failure

Dalton, Laurin1; Blackford, Jennifer1; Carey, Ryan1; Moran, Amy1; Nelson, Steve1; Lowe, Dawn1 Author Information

Estradiol Replacement in Ovariectomized Rats Is Antihyperalgesic in the Formalin Test

A subcutaneous implant of 17beta-estradiol or progesterone provides steady-state serum hormone levels from 7 to 24 days after implantation and allows the evaluation of the effects of the replacement with these hormones on phase 1 and phase 2 formalin-induced behaviors in ovariectomized (OVX) rats. Graded doses of 17beta-estradiol (5% to 40%) reduce formalin-induced behavior by 35% to 49% during phase 2 but not during phase 1, as measured with an automated formalin apparatus. The maximal response is seen with 20% 17beta-estradiol. The antihyperalgesic effect of 20% 17beta-estradiol is significant at 8 days after implantation and persists at 21 days. In contrast, graded doses of progesterone have no effect on either phase of formalin. The estrogen receptor antagonist tamoxifen completely prevents the antihyperalgesic effect of the 20% 17beta-estradiol implant. Formalin-induced behaviors during phase 2 are significantly less in proestrus females and OVX rats given 20% 17beta-estradiol compared with OVX control rats. Also, the formalin-induced increase in serum corticosterone is attenuated in OVX control rats compared with proestrus females and OVX rats given 20% 17beta-estradiol. These results indicate that estrogen replacement in OVX rats restores the maximal corticosterone response to tonic pain and, by an estrogen receptor-mediated process, inhibits tonic pain. Hormone replacement (HR) therapy remains a widely used modality. We used a pharmacokinetically based rat HR model that results in continuous physiological levels of 17beta-estradiol to demonstrate the analgesic (antihyperalgesic) effects of estrogen replacement in an inflammatory pain model (formalin). These results suggest a potentially important consequence of HR therapy.

Effect of estrogen replacement on the circadian rhythms of feeding, activity and body temperature in ovariectomized rats

Effect of estrogen replacement on the circadian rhythms of feeding, activity and body temperature in ovariectomized rats

Effects of Estrogen Replacement on Voluntary Aerobic Exercise and Body Weight in an Animal Model of Menopause

Forstner, Jeffrey P.1; Gorzek, Jeffrey F.1; Hendrickson, Kaysie C.1; Rixen, Jennifer L.1; Moran, Amy L.1; Lowe, Dawn A.1 Author Information

Inhibitory effect of low-dose estrogen on neointimal formation after balloon injury of rat carotid artery

The current regimens of hormone replacement therapy for postmenopausal women, estrogen combined with progestogen, have failed to show beneficial effects for the prevention of atherosclerotic disease. Although the relatively higher dose of estrogen contained in those regimens exerted adverse effects, there are few data examining a lower dose of estrogen in an atherosclerosis model. Therefore, we investigated experimentally whether lower doses of estrogen could inhibit neointimal formation after balloon injury of the rat carotid artery. Ten-week-old Wistar rats were subjected to ovariectomy or sham-operation ( n=7). Four days after ovariectomy, rats were implanted with an osmotic mini-pump containing 17-β estradiol (0.2, 1, 2, 10 and 20 μg/kg/day; n=6, 4, 8, 6 and 5, respectively) or placebo ( n=10). After 3 days of hormone therapy, balloon injury was performed in the left common carotid artery. Neointimal formation was histologically evaluated 2 weeks after injury. Cross-sectional intimal area and the ratio of intimal area to medial area were dose-dependently reduced by estrogen replacement compared with those in ovariectomized rats without estrogen replacement. The effects of estrogen replacement were identical to those of an angiotensin II type 1 receptor blocker, candesartan. Interestingly, the effect was significant even in rats receiving lower doses of estrogen, in which plasma estradiol concentrations were not increased and the hyperplastic response of the uterus was minimal. These results suggest the efficacy of low-dose estrogen therapy for the protection of atherosclerosis.