Estrogen Replacement Therapy Group Research Articles

Effects of ovariectomy and estrogen replacement therapy on arthritis and bone mineral density in rats with collagen-induced arthritis

We investigated the effects of ovariectomy (ovx) and estrogen replacement therapy (ERT) on bone mineral density (BMD) and arthritis severity in rats with collagen-induced arthritis (CIA). Seven-month-old female Sprague-Dawley rats were separated into a sham group (n = 8), CIA group (n = 14), ovx group (n = 10), CIA + ovx group (n = 11), and CIA + ovx + ERT group (n = 14). In these groups, ovx was performed at 7 days, and ERT (17β-estradiol at 20 μg/kg three times per week) was initiated 8 days after sensitization. Every 2 weeks, until 8 weeks after sensitization, arthritis score and hind paw thickness were evaluated, and BMD of the trabecular and cortical bones in the metaphysis and diaphysis of the tibia were measured by peripheral quantitative computed tomography. The arthritis score was highest in the CIA + ovx group at all timepoints after sensitization. The hind paw thickness was significantly higher in the CIA + ovx group than in the CIA group at 8 weeks after sensitization ( p < 0.05). Both the arthritis score and hind paw thickness were lower in the CIA + ovx + ERT group than in the CIA + ovx group. BMD in the metaphysis was significantly decreased in both the trabecular and cortical bones in the CIA + ovx group compared with those in the CIA group at 4, 6, and 8 weeks after sensitization. In the CIA + ovx group, trabecular BMD was changed by −34 ± 11%, and cortical BMD changed by −14 ± 7% in the metaphysis at 8 weeks compared with those at 0 week. In the CIA group, changes of BMD in the metaphysis were −7 ± 11% in trabecular bone and 0 ± 7% in cortical bone. These differences of trabecular and cortical bone loss in the metaphysis were significant (both p < 0.01). BMD reduction was significantly less in the CIA + ovx + ERT group than in the CIA + ovx group at 6 and 8 weeks after sensitization. Although BMD in the diaphysis was also reduced in the groups with CIA, the degree of reduction was smaller than in the metaphysis. We conclude that ovx in CIA rats could enhance the severity of arthritis and bone loss, and that ERT could suppress arthritis and bone loss.

Urinary free cortisol and sleep under baseline and stressed conditions in healthy senior women: effects of estrogen replacement therapy.

The purpose of this study was to examine the effects of a mild 24-h stress (indwelling IV catheter) on cortisol and sleep in postmenopausal women, and to evaluate differences due to estrogen replacement therapy (ERT) status. This study, conducted in the General Clinical Research Center at the University of Washington Medical Center, examined sleep, cortisol and sleep-cortisol relationships in both baseline and stress conditions, and compared women on ERT with women not on ERT. Forty-two women (age=69.6 +/- 6.2 years [SD]), of whom 20 were on ERT, participated. Urinary free cortisol (UFC) levels and sleep polysomnography were measured over both 24-baseline and stress condition. Sleep was impaired in the stress condition for both groups; mean UFC levels were higher, sleep efficiency and minutes of stages 2, 3 and 4 sleep were reduced, and morning risetime was earlier in the stress than baseline condition. For the combined groups, age-controlled correlations between 24-h UFC and sleep were significant in both conditions: at baseline, UFC levels were associated with earlier time of rising and less REM sleep, and under stress with reduced sleep efficiency, there was reduced minutes of stages 2, 3, 4 sleep, reduced REM sleep, and an earlier risetime. The pattern of negative significant correlations between UFC and sleep/sleep timing remained when plasma estrogen was statistically controlled; however, when groups were examined separately, the significant negative UFC-sleep relationships were confined to the non ERT group. Elevated 24-h UFC is associated with impaired sleep and earlier awakening in older women not on ERT, but not in women on ERT.

Laryngeal cytological aspects in women with surgically induced menopause who were treated with transdermal estrogen replacement therapy

Objective: To investigate the effects of estrogen replacement therapy (ERT) on laryngeal cytology in postmenopausal women. Design: Prospective open clinical trial. Setting: Outpatient menopausal clinic in the Department of Gynecology, University of Catania, Catania, Italy. Patient(s): Eighty-four healthy, surgically postmenopausal women, of whom 48 were treated with ERT and 36 were considered as a control group. Intervention(s): Transdermal E 2 treatment by patches or gel, evaluation of laryngeal cytology with cytobrush by indirect laryngoscopy, and questionnaire for the voice history. Main Outcome Measure(s): Changes in cytologic aspects of laryngeal cells with respect to vaginal cytology by hematoxylin and eosin staining; subjective voice changes. Result(s): Sixty-seven women completed the study. Ten women from the ERT group and five from the control group dropped out because of the invasive laryngoscope method; two subjects in the control group were excluded because of pathologies of the vocal cord. Hematoxylin and eosin staining confirmed similar superficial-intermediate aspects of the cells between the laryngeal and the vaginal smears in ERT-treated women. In the control group, both smears showed aspects of atrophy-dystrophy. The ERT group had a subjectively better quality of voice than the control group. Conclusion(s): Our study confirms that the larynx is an estrogen target, as are vaginal cells. ERT may provide prevention and treatment of dystrophic pathologies of the vocal cords in postmenopausal women.

In reply:

In reply: We previously reported that in a large, nondemented, community cohort of older, white women, both current users of estrogen replacement therapy (ERT) and never users had similar declines in cognitive test scores across a 6-year period1 and that high education attainment was, after age, the most powerful predictor of good cognitive function. Drs. Cunningham, O'Neill, and Rowan suggest that the protective effect of ERT on cognitive decline may have been obscured by incomplete follow-up of the cohort. Although follow-up was quite reasonable considering the women's age, nearly 7% died between examinations, and an additional 16% were not re-examined. Those who participated were younger, more educated, more likely to use ERT, and performed better on the cognitive tests at the initial examination relative to participants. We noted (p. 522; 1) that “As a consequence, we could only test our hypotheses in a better functioning group.” It is not possible to know how differential loss to follow-up affects our results. Survival may be better among both those who use ERT and those with preserved cognitive function,2-4 with the result that women using ERT and those having better cognitive function were being more likely to be alive and able to participate in our follow-up examination. This type of bias would lead to an overestimation of a protective effect of ERT. On the other hand, if women who are having memory problems are being prescribed ERT by their physicians or are reporting incorrectly that they are on ERT, then women with low cognitive function would be in the ERT group, leading to an underestimation or negative effect of ERT. Note that the prospective studies5, 6 showing a protective effect of ERT did not have complete follow-up of women because the eligibility criteria included follow-up examinations. Our study did not use the full Mini-Mental Status Examination, and scores ranged from 0 to 26 rather than 0 to 30. Therefore, comparisons of our findings with others based on cutoffs of less than 24 cannot be made. The studies5, 6 showing a protective effect of ERT examined risk of developing Alzheimer's disease (AD), not change in cognitive scores as in our study. The biological determinants of AD may differ from the determinants of cognitive decline in older people. Two large cohort studies did show that ERT users exhibited less cognitive decline over time in unadjusted analyses.7, 8 However, one did not adjust for potential confounders,7 and the effect for ERT became nonsignificant in the second after adjustment for education.8 Our conclusion is that the most powerful intervention for protecting older women from cognitive decline may be education, not the use of ERT. Clinical trials are needed to evaluate both the effects of late-life education and the use of ERT.

Indirect evidence that estrogen replacement therapy stimulates nitric oxide synthase in postmenopausal women

The aim of the study was to investigate the effects of estrogen replacement therapy (ERT) on nitric oxide (NO) activity in healthy postmenopausal women.The study group consisted of 22 postmenopausal women (last menses at least 12 months prior to study entry) who were randomized to receive treatment for 2 months with patches that delivered either 50 μg/day of 17β-estradiol or placebo in a cross-over design. Blood samples for measurements of serum citrulline and arginine were collected at the start of the study and at the end of each treatment course. Serum citrulline and arginine were measured using high-performance liquid chromatography with fluorometric detection.Arginine levels were significantly lower in the ERT group compared to the placebo group, while citrulline levels did not change. The percentage citrulline/arginine ratio was significantly higher in the ERT group (42.9 ± 21.6) compared to the placebo group (33.9 ± 18.5) (p < 0.01). The citrulline/arginine ratio, both at baseline and during either ERT or placebo administration demonstrated a positive linear correlation with body mass index (BMI). No correlations were found between follicle stimulating hormone, estradiol and insulin levels and BMI. No correlations were found between age, time since menopause and baseline arginine and citrulline levels or the citrulline/arginine ratio.These data indirectly demonstrate that transdermal estradiol replacement in postmenopausal women is able to stimulate NO production through the involvement of endogenous L-arginine. A positive linear correlation was found between BMI and the citrulline/arginine ratio, suggesting an additional protective cardiovascular effect in overweight women.

Estrogen Replacement Therapy, Serum Lipids, and Polymorphism of the Apolipoprotein E Gene

Pharmacogenomics, the study of genetic loci that modulate drug responsiveness, may help to explain why estrogen replacement therapy (ERT) has differential effects on serum lipid and lipoprotein concentrations in postmenopausal women who inherit distinct alleles of the apolipoprotein E gene (APOE). We compared total-cholesterol, triglyceride, and lipoprotein (LDL and HDL) concentrations in 66 postmenopausal women receiving ERT ([+]ERT) with 174 postmenopausal women not receiving ERT ([-]ERT), controlling for three APOE genotypes divided into three groups: E2 (epsilon2/epsilon3, n = 31), E3 (epsilon3/epsilon3, n = 160), and E4 (epsilon3/epsilon4 + epsilon4/epsilon4, n = 49). Mean total-cholesterol concentrations were lower in all three [+]ERT groups compared with their [-]ERT counterparts but were statistically significant only for women in group E4 (P = 0.014). The mean LDL-cholesterol concentrations were significantly lower in all three [+]ERT groups compared with their [-]ERT counterparts (P </=0.005). Although all three groups of [+]ERT women tended to have higher mean HDL-cholesterol concentrations compared with their [-]ERT counterparts, the differences were not statistically significant. [+]ERT women in groups E2 and E3 had significantly higher (P <0.05) triglyceride concentrations than their [-]ERT counterparts. In [+]ERT women, the ratios of total and LDL-cholesterol to HDL-cholesterol were significantly higher in group E3 and E4 women compared with E2 women (P <0.006). Group E4 [+]ERT women had ratios of total and LDL-cholesterol to HDL-cholesterol that were comparable to group E2 [-]ERT women. Triglyceride concentrations in group E2 [+]ERT women may need to be monitored more closely than those in E3 or E4 [+]ERT women. Group E4 women should probably be targeted for ERT. Results suggest that APOE genotypes have a differential effect on serum lipids and lipoproteins in [+]ERT postmenopausal women.

Estrogen Replacement Therapy After Localized Breast Cancer: Clinical Outcome of 319 Women Followed Prospectively

To determine whether estrogen replacement therapy (ERT) alters the development of new or recurrent breast cancer in women previously treated for localized breast cancer. Potential participants (n = 319) in a trial of ERT after breast cancer were observed prospectively for at least 2 years whether they enrolled onto the randomized trial or not. Of 319 women, 39 were given estrogen and 280 were not given hormones. Tumor size, number of lymph nodes, estrogen receptors, menopausal status at diagnosis, and disease-free interval at the initiation of the observation period were comparable for the trial participants (n = 62) versus nonparticipants (n = 257) and for women on ERT (n = 39) versus controls (n = 280). Cancer events were ascertained for both groups. Patient and disease characteristics were comparable for the trial participants versus nonparticipants, as well as for the women on ERT versus the controls. One patient in the ERT group developed a new lobular estrogen receptor-positive breast cancer 72 months after the diagnosis of a ductal estrogen receptor-negative breast cancer and 27 months after initiation of ERT. In the control group, there were 20 cancer events: 14 patients developed new or recurrent breast cancer at a median time of 139.5 months after diagnosis and six patients developed other cancers at a median time of 122 months. ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer. Results of randomized trials are needed before any changes in current standards of care can be proposed.

Estrogen therapy for depression in postmenopausal women

Objective: To look at the modification in depressive mood in postmenopausal depressed women after estrogen replacement therapy (ERT). Method: Twelve depressed patients divided into two groups of six women each were studied. One group received conjugated equine estrogens (CEE) 0.625 mg/day; the other did not receive any treatment (control group). Mood was assessed in all the subjects at baseline and at 6 months with Hamilton Rating Scale score and considered as depression when it was >15. Differences between groups were determined by Mann–Whitney U-test, and in each group between baseline and 6-month values with Wilcoxon test. Results: The ERT group had a statistically significant decrease in depressive mood (21 vs. 13 points, P<0.03), while in the control group no significant change was found. Final Hamilton scale scores were significantly lower ( P<0.05) in those under ERT, when compared with those in the control group. Conclusion: Depressive mood decreased after 6 months with CEE, so the prescription of ERT can be useful in postmenopausal women with depressive mood.

Differential time-related effects of conjugated equine estrogen on bone metabolism in oophorectomized women

Objective: The effects of conjugated equine estrogen (CEE) on bone mineral density (BMD) and biochemical indices of bone remodeling in oophorectomized women were studied for 3 years during estrogen replacement therapy (ERT) to investigate whether 0.625 mg/day of CEE alone prevent acute bone loss in the early stage of surgical menopause. Methods: We divided the subjects into three groups according to interval between oophorectomy and the start of ERT (group 1: less than 2 years after surgery, n = 31; group 2: 2–5 years after surgery, n = 29; and group 3: more than 5 years after surgery, n = 27). Vertebral BMD was measured using dual energy X-ray absorptiometry (DEXA). Two biochemical indices of bone metabolism, urinary deoxypyridinoline (DPyr) and serum intact human osteocalcin (hOC) were also measured. Results: In group 1, continuous ERT with 0.625 mg/day of CEE could not prevent a BMD decrease within the first year. However, by the end of the second year, BMD was restored to the pre-ERT. The same dosage of CEE significantly increased BMD in groups 2 and 3 by the end of the first year. DPyr and hOC levels both decreased dramatically in the initial 6 months of therapy and were stable thereafter. Conclusion: In the initial 2-year period after oophorectomy, 0.625 mg/day of CEE alone could not prevent acute bone loss suggesting that additional therapy for the prevention of osteoporosis may be needed.

Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women.

This investigation examined effects of chronic (>/=2 yr) hormone replacement therapy (HRT), both estrogen replacement therapy (ERT) and estrogen plus progesterone therapy (E+P), on core temperature and skin blood flow responses of postmenopausal women. Twenty-five postmenopausal women [9 not on HRT (NO), 8 on ERT, 8 on E+P] exercised on a cycle ergometer for 1 h at an ambient temperature of 36 degrees C. Cutaneous vascular conductance (CVC) was monitored by laser-Doppler flowmetry, and forearm vascular conductance (FVC) was measured by using venous occlusion plethysmography. Iontophoresis of bretylium tosylate was performed before exercise to block local vasoconstrictor (VC) activity at one skin site on the forearm. Rectal temperature (Tre) was approximately 0.5 degrees C lower for the ERT group (P < 0.01) compared with E+P and NO groups at rest and throughout exercise. FVC: mean body temperature (Tb) and CVC: Tb curves were shifted approximately 0.5 degrees C leftward for the ERT group (P < 0.0001). Baseline CVC was significantly higher in the ERT group (P < 0.05), but there was no interaction between bretylium treatment and groups once exercise was initiated. These results suggest that 1) chronic ERT likely acts centrally to decrease Tre, 2) ERT lowers the Tre at which heat-loss effector mechanisms are initiated, primarily by actions on active cutaneous vasodilation, and 3) addition of exogenous progestins in HRT effectively blocks these effects.

Long-term estrogen therapy abolishes acute estrogen-induced coronary flow augmentation in postmenopausal women

Postmenopausal estrogen replacement therapy (ERT) may reduce the clinical manifestations of coronary heart disease by favorably modulating coronary vasoreactivity. Intravenous ethinyl estradiol acutely increases coronary flow in postmenopausal women not receiving ERT. Because several vasoactive agents induce vasomotor tolerance when administered on a long-term basis, we hypothesized that long-term ERT attenuates the acute coronary vasomotor effects of intravenous ethinyl estradiol. To test this hypothesis, coronary hemodynamics were determined before and 15 minutes after intravenous ethinyl estradiol (35 μg) in 10 postmenopausal women who were receiving long-term conjugated ERT (group 1) and 10 who had never received ERT (group 2). Estradiol administration in group 1 was not associated with significant changes in coronary flow or resistance. However, women in group 2 exhibited a 28.6% ± 6.5% ( p < 0.001) increase in coronary flow and a 19.9% ± 3.5% ( p = 0.008) decrease in resistance. These results demonstrate that long-term ERT significantly attenuates the response of coronary arteries to the acute vasomotor effects of a high dose of estradiol. This response may be caused by long-term estrogen-induced coronary flow augmentation or to the development of vasomotor tolerance to estrogen. (Am Heart J 1997;133:323-8.)

Estrogen replacement in surgical stage I and II endometrial cancer survivors

OBJECTIVE: Our purpose was to evaluate our experience with estrogen replacement in women with a history of early-stage endometrial cancer and to determine whether it increased the risk for recurrence or death. STUDY DESIGN: A retrospective review was performed of 123 women with surgical stage I and II endometrial adenocarcinoma treated between 1984 and 1994; 62 had received estrogen replacement therapy after cancer therapy. Sixty-one women received no estrogen. Variables analyzed included age, parity, surgical stage, grade, depth of myometrial invasion, presence of intercurrent illnesses, duration of follow-up, and duration of estrogen replacement, if applicable. Outcome variables assessed included recurrence rate, time to recurrence, and disease-free interval. RESULTS: The estrogen replacement therapy group had earlier stage disease ( p = 0.04) and less severe depth of invasion ( p = 0.003); however, the total number of deaths in each group was not significantly different. The disease-free survival in the estrogen replacement therapy group did not differ significantly compared with those not receiving estrogen replacement therapy. The data are suggestive of improved disease-free survival in the estrogen replacement therapy group, which may be related to differences in age, stage, grade, and depth of invasion. The overall recurrence rate was 6.5%, with an overall death rate of 1.6%. CONCLUSIONS: There is no evidence to suggest that estrogen decreased the disease-free interval or increased the risk for recurrence in early-stage disease. (Am J Obstet Gynecol 1996;175:1195-200.)

Postmenopausal estrogen replacement: A long-term cohort study

To assess the long-term effects of estrogen replacement therapy (ERT) in 157 post-menopausal women, a prospective, non-randomized, cohort study was conducted from 1964 to 1989. ERT consisted of 0.625 mg of conjugated equine estrogen daily for the first 25 days of each month without oral progesterone from 1964 to 1984. From 1984 to 1989 5 mg of medroxyprogesterone was added from day 14 to 25 of every sixth month in subjects with an intact uterus. The mean loss of height was significantly less among the ERT subjects after age 65 years and remained at 0.08 cm/year from age 56 to 80 years, whereas the loss of height accelerated among the control subjects to 0.19 cm/year from age 66 to 70, to 0.22 cm/year from age 71 to 75, and to 0.30 cm/year from age 76 to 80. The mean cortical bone density at the distal third of the radius was significantly greater among the ERT subjects compared to the control subjects with the difference representing a 12.0% higher bone density with ERT. The risk of both vertebral compression and peripheral fractures was significantly reduced in the ERT group (relative risk 0.28). The mean serum LDL cholesterol was 21% lower and the mean HDL cholesterol, 37% higher among ERT subjects compared to control subjects. Both ERT and total serum cholesterol had independent effects on the development of cardiovascular disease (myocardial infarction and stroke) in a multivariate analysis.

Effects on bone of surgical menopause and estrogen therapy with or without progesterone replacement in cynomolgus monkeys

The influence of estrogen replacement therapy on bone loss of surgically postmenopausal cynomolgus macaques was evaluated histomorphometrically using the first (L-1) lumbar vertebra and ex vivo dual photon absorptiometry of the third (L-3) lumbar vertebra. The animals were a subgroup of a larger study on the effects of estrogen replacement therapy on diet-induced coronary artery atherosclerosis. The three experimental conditions were as follows: untreated females with oophorectomy, females with oophorectomy treated with continuous estrogen replacement therapy plus cyclic progesterone, and females with oophorectomy treated with estrogen replacement therapy. Bone mineral density (grams per square centimeter) of L-3, when covaried for body mass index (body mass index, body weight/(trunk length/100)2), was significantly lower for the oophorectomy group compared with the group treated by estrogen replacement therapy plus progesterone and estrogen replacement therapy groups (p = 0.018). When covaried for body mass index, trabecular bone volume percentage of a midsagittal section of L-1 was not significantly different between groups, but the adjusted mean was greatest in the estrogen replacement therapy plus progesterone group, followed closely by the estrogen replacement therapy group, and was least in the oophorectomy group. When covaried for body mass index, trabecular plate number was significantly lower (p = 0.022) and mean trabecular plate separation was significantly higher (p = 0.033) in the oophorectomy group. Thus both estrogen replacement therapy and estrogen replacement therapy plus progesterone provided overall protection against surgical menopause-associated bone mass loss. Cynomolgus macaques are an extremely useful animal model for estrogen replacement therapy use in prevention of postmenopausal bone loss.