Prevalence of estrogen or estrogen-progestin hormone therapy use

OBJECTIVE: To use nationally representative data to produce prevalence estimates of combination estrogen-progestin therapy and estrogen-only therapy by covariates, and to evaluate differences between current use of short duration (less than 5 years) and current long-term use. METHODS: We analyzed data from female respondents 40 years of age and older (n = 9400) who were interviewed in the 1999 National Health Interview Survey. Hormone therapy use was categorized into four types: current estrogen-progestin therapy use, current estrogen-only therapy use, former hormone therapy use, and never use. We calculated the prevalence of hormone therapy by different levels of previously identified covariates of hormone therapy, as well as overall prevalence of hormone therapy use by length of use. RESULTS: Approximately 24% of women aged 40 years or older were current hormone users. Of these, 30% were taking estrogen-progestin therapy, and 70% were taking estrogen-only therapy. The prevalence of hormone use differed dramatically by hysterectomy status and age, and less so by many demographic, health-risk behavior, medical access, and medical history variables. Among women with no hysterectomy, the associations with many of the covariates were stronger for estrogen-progestin therapy use than for estrogen-only therapy use. Only 3% of women were estimated to be current estrogen-progestin therapy users for 5 or more years, whereas 10% were current estrogen-only therapy users for 5 or more years. CONCLUSION: Although many women at midlife and older were current hormone users, very few were long-term users of estrogen-progestin therapy.     

Long-term effects of tibolone on mammographic density

OBJECTIVE: To investigate the long-term effect of tibolone on mammographic density. DESIGN: Open-label, nonrandomized study. SETTING: Academic research environment. PATIENT(S): Postmenopausal women. INTERVENTION(S): Tibolone was administered orally, mammograms were performed annually. MAIN OUTCOME MEASURE(S): Mammographic density according to the Wolfe classification, performed by two independent radiologists, both of whom were blinded to treatment group. RESULT(S): No statistically significant differences were found between the two groups in baseline demographic data. There were no statistically significant differences in mammographic density between the control and active groups at baseline or at 10 years. CONCLUSION(S): This pilot study shows that tibolone does not adversely alter the mammographic density of the breasts over 10 years of treatment.     

The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa

INTRODUCTION: Osteopenia is a serious complication of anorexia nervosa (AN). Although in other states of estrogen deficiency, estrogen replacement therapy increases bone mass, its role in AN remains unresolved. STUDY OBJECTIVE: To study the effect of estrogen-progestin administration on bone mass in AN. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study of 50 adolescents with AN (mean age 16.8 +/- 2.3 yrs) was conducted in a tertiary referral center. MAIN OUTCOME MEASURES: Bone mineral density (BMD) of the lumbar spine and left hip were prospectively measured using dual-energy x-ray absorptiometry at baseline and annually. INTERVENTIONS: Twenty-two subjects received estrogen-progestin and 28 standard treatment (Rx) alone. Estrogen-progestin was administered daily as an oral contraceptive containing 20-35 mcg ethinyl estradiol. All subjects received calcium supplementation and the same medical, psychological, and nutritional intervention (standard Rx). Mean length of follow-up was 23.1 +/- 11.4 months. RESULTS: At presentation, patients were malnourished (79.5% +/- 7.6% IBW), hypoestrogenemic (estradiol 24.7 +/- 10.7 pg/mL), and had reduced bone mass (lumbar spine BMD -2.01 +/- 0.69 SD below the young adult reference mean). Ninety-two percent of subjects were osteopenic and 26% met WHO criteria for osteoporosis. Body weight, and no treatment group, was the major determinant of BMD. At one-year follow-up, there were no significant differences in absolute values or in net change of lumbar spine or femoral neck BMD between those who received estrogen-progestin and those who received standard Rx (80% power of finding a 3% difference in BMD at 1 yr). In those followed for 2-3 yrs, osteopenia was persistent and in some cases progressive. CONCLUSION: In our study population, estrogen-progestin did not significantly increase BMD compared with standard Rx. These results question the common practice of prescribing hormone replacement therapy to increase bone mass in AN.     

The differential effect of estrogen, estrogen-progestin and tibolone on coagulation inhibitors in postmenopausal women.

OBJECTIVES: Hormone therapy increases the risk of venous thromboembolism, possibly through a negative effect on coagulation inhibitors. The aim of the study was to assess the effect of conjugated equine estrogens alone or in combination with medroxyprogesterone acetate, low-dose 17beta-estradiol combined with norethisterone acetate and tibolone on inhibitors of coagulation. METHODS: Two hundred and sixteen postmenopausal women received orally either conjugated equine estrogens 0.625 mg (CEE, n=24) or tibolone 2.5 mg (n=24) or CEE+medroxyprogesterone acetate 5 mg (CEE/MPA, n=34) or 17beta-estradiol 1 mg+norethisterone acetate 0.5 mg (E2/NETA, n=66) or no therapy (control, n=68) for 12 months. Plasma antithrombin, protein C and total protein S were measured at baseline and at 12 months. RESULTS: CEE, CEE/MPA and E2/NETA treatment were associated with a significant decrease in antithrombin levels (CEE: baseline 235.6+/-47.6 mg/l, follow-up 221.3+/-48.3 mg/l, p=0.0001; CEE/MPA: baseline 251.1+/-38.6 mg/l, follow-up 225.0+/-42.6 mg/l, p=0.009; E2/NETA: baseline 257.1+/-59.4 mg/l, follow-up 227.1+/-50.4 mg/l, p=0.007; tibolone: baseline 252.6+/-62.4 mg/l, follow-up 261.9+/-59.1 mg/l, p=0.39). Protein C decreased significantly in the CEE and CEE/MPA groups (CEE: baseline 3.64+/-1.17 mg/l, follow-up 2.48+/-1.47 mg/l, p=0.004; CEE/MPA: baseline 3.24+/-1.23 mg/l, follow-up 2.61+/-1.38 mg/l, p=0.001; E2/NETA: baseline 3.24+/-1.10 mg/l, follow-up, 3.15+/-1.11 mg/l, p=0.08; tibolone: baseline 3.26+/-1.25 mg/l, follow-up 3.09+/-1.32 mg/l, p=0.37). Protein S decreased significantly only in the CEE/MPA group (CEE: baseline 19.4+/-2.76 mg/l, follow-up 18.0+/-2.45 mg/l, p=0.56; CEE/MPA: baseline 18.4+/-3.42 mg/l, follow-up 14.5+/-3.43 mg/l, p=0.005; E2/NETA: baseline 19.0+/-3.11 mg/l, follow-up 19.5+/-3.43 mg/l, p=0.18; tibolone: baseline 18.5+/-3.09 mg/l, follow-up 18.0+/-4.09 mg/l, p=0.32). CONCLUSIONS: Estrogen and estrogen-progestin therapy are associated with a reduction in coagulation inhibitors, the extent of which depends on the regimen administered. Tibolone appears to have no effect on inhibitors of coagulation.     

Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density

OBJECTIVE: Our purpose was to compare the effects of tibolone, continuous combined hormone replacement therapy, and placebo on mammographic breast density. STUDY DESIGN: A prospective, randomized, double-blind placebo-controlled study was performed. A total of 166 postmenopausal women were equally randomized to receive tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E(2)/NETA), or placebo. Mammograms were performed at baseline and after 6 months of treatment. Mammographic density was quantified according to the Wolfe classification and by the percentage area of the breast that had a dense pattern. RESULTS: An increase in mammographic density was much more common among women receiving continuous combined hormone replacement therapy (46%-50%) than among those receiving tibolone (2%-6%) and placebo (0%) treatment. The difference between E(2)/NETA and placebo was highly significant (P <.001). Treatment with tibolone did not differ from that with placebo. The relative risk of an increase in breast density for E(2)/NETA versus tibolone was found to be 8.3 (95% CI 2.7-25.0). CONCLUSION: An increase in mammographic density should be regarded as an unwanted side effect of hormone replacement therapy. In contrast to estrogen/progestogen treatment, tibolone seems to exert little stimulation of breast tissue.     

Different effects of tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels--an association with mammographic density.

OBJECTIVE: To compare the effects of tibolone and continuous combined hormone therapy on circulating sex steroids and their binding proteins and their relationship to mammographic density. STUDY DESIGN: A prospective, double-blind placebo-controlled study. A total of 166 postmenopausal women were equally randomized to receive tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA) or placebo. Serum analyses of sex steroids, insulin-like growth factor (IGF-I) and binding proteins and assessment of mammographic breast density were performed at baseline and after 6 months of treatment. RESULTS: Estrogens were markedly increased and androgens decreased by E2/NETA. In contrast, tibolone had only a minor influence on circulating estrogens. Sex hormone binding globulin (SHBG) levels were reduced by 50%, while levels of androgens increased. Baseline values of estrone sulfate (E1S), around 1.0-1.1 nmol/l, were increased to 44.7 nmol/l by E2/NETA and to only 1.7 nmol/l by tibolone (p < 0.001). Mammographic breast density displayed a negative correlation with age and body mass index and a positive association with SHBG. After 6 months there was also a negative correlation with levels of free testosterone.Conclusion We found that tibolone and E2/NETA caused distinct differences in estrogen/androgen status and blood levels of possible breast mitogens. The negative association between free testosterone and mammographic density could be a possible explanation for tibolone having less influence on the breast.     

Effects of a short-term suspension of hormone replacement therapy on mammographic density

OBJECTIVE: To evaluate the effects of hormone replacement therapy (HRT) and of a short-term suspension of HRT on mammographic density. DESIGN: Prospective clinical study. SETTING: Outpatient menopausal clinic of the Second University of Naples. PATIENT(S): Ninety-seven healthy postmenopausal women. INTERVENTION(S): Thirty-nine menopausal women with intact uterus (group A) were treated with continuous transdermal E(2) plus acetate nomegestrolo sequentially added, 37 women in surgical menopause (group B) were treated with transdermal E(2) continuously administered, and 21 menopausal women did not receive any medication (group C). At the entry and after 12 months, a mammography was performed without suspension of HRT (group A1: 19 women; group B1: 19 women) or after a short-term suspension (group A2: 20 women; group B2: 18 women). MAIN OUTCOME MEASURE(S): Mammographic density evaluated according to a quantitative method. RESULT(S): At the second mammography, seven patients in group A1, four patients in group B1, and one patient in both groups A2 and B2 showed an increase in mammographic density, whereas no mammographic density increase was observed in patients in group C. A statistically significant difference in the mammographic density increase was found between group A1 and group A2; no difference was found between group B1 and B2. CONCLUSION(S): Suspension of HRT for about 3 weeks may reverse mammographic density increase associated with its use.     

Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density.

OBJECTIVE: To compare the effects of two different ultra-low doses of continuous combined hormone therapy and placebo on mammographic breast density in postmenopausal women. METHODS: A subpopulation of 255 postmenopausal women from the CHOICE trial were randomly assigned to 0.5 mg 17beta-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA, or placebo. Women using hormone replacement therapy (HRT) up to 2 months prior to the study were excluded; 154 women fulfilled the inclusion criteria. Mammograms were performed at baseline and after 6 months. Breast density was evaluated by visual classification scales and a computer-assisted digitized technique. RESULTS: No significant differences were detected between the active treatment groups and the placebo group in the digitized quantification. The mean baseline values for density around 20% were unchanged after 6 months. Also, visual classifications showed no increase in breast density in any study group. CONCLUSION: In contrast to currently available bleed-free regimens, the new ultra-low-dose combination of 0.5 mg E2 and 0.1 mg NETA seems to have very little or even a neutral effect on the breast. Both digitized quantification and visual assessment of breast density were unchanged after 6 months. Larger prospective studies should be performed to confirm this new finding.     

Testosterone addition during menopausal hormone therapy: effects on mammographic breast density.

OBJECTIVE: To study the effect on mammographic breast density of testosterone addition during combined estrogen/progestogen therapy in postmenopausal women. METHODS: A prospective, randomized, double-blind, placebo-controlled trial. A total of 99 women were given 2 mg 17beta-estradiol and 1 mg norethisterone acetate in combination with either a testosterone patch (300 mug/24 h) or a placebo patch. Mammographic breast density at baseline and after 6 months was assessed by visual classification scales and by digitized quantification. A standardized questionnaire was used to quantify subjective breast symptoms. RESULTS: Visual classifications showed an increase in mammographic density in 18-30% of the women, with no significant differences between the treatment groups. The mean increase of the area of dense breast during treatment according to digitized assessment was 7.4% in the placebo group and 5.4% in the testosterone group. Breast symptoms showed a positive association with the increase in density (r(s) = 0.34; p < 0.01). Symptoms were most pronounced at 2 months of treatment. Density, both at baseline (r(s) = -0.35; p < 0.01) and change during treatment (r(s) = -0.28; p < 0.01) showed a negative association with free testosterone levels. CONCLUSION: The addition of testosterone does not appear to influence mammographic breast density in women concurrently treated with a common oral estrogen/progestogen regimen for a period of 6 months.     

Estradiol plus drospirenone therapy increases mammographic breast density in perimenopausal women

Objective

To investigate the effects of 17β-estradiol 1 mg plus drospirenone 2 mg (E2/DRSP) treatment on mammographic breast density in perimenopausal women.

Study design

In this prospective study, 80 healthy perimenopausal women aged 41–49 years were enrolled and assigned to either E2/DRSP (n = 40) or a control group (n = 40). Mammograms were performed at baseline and after 12 months of treatment. Mammographic breast density was quantified according to the Wolfe classification.

Results

We demonstrated an increase in mammographic breast density in 37% (95% CI (confidence interval): 18.8–55.3%) of women treated with E2/DRSP after 12 months. The percentage of women with increased density was 0% (95% CI: 0.0–0.0%) in the control group. The difference in breast density between the E2/DRSP group and the control group was statistically very significant (p < 0.001).

Conclusions

E2/DRSP therapy for 12 months in perimenopausal women significantly increased mammographic breast density in comparison to a control group. Further long-term and large scale prospective studies are needed to evaluate this issue.     

Effects of hormone replacement therapy regimens on mammographic breast density: the role of progestins

AIM: To evaluate the effects of different regimens of hormone replacement therapy (HRT) on mammographic breast density. METHODS: Mammograms of 113 healthy postmenopausal women who were on different HRT regimens were evaluated retrospectively. All women had a baseline mammography and at least one mammogram after at least 12 months of HRT. Four parenchymal patterns were considered mammographically. Quantification of density changes that occurred on follow-up mammograms was done qualitatively and with reference to densities on baseline mammograms. RESULTS: Sixty women were treated with a continuous estrogen-progestin combination; 16 with a cyclic estrogen-progestin combination and 37 were with estrogen only. Twenty-six women had increased mammographic density after HRT. Mammographic density increase was detected in 23 women (38.3%) of the continuous estrogen-progestin combination group, two women (12.5%) of the cyclic estrogen-progestin combination group and one woman (2.7%) of the estrogen-only group. Mammographic density increase was more common among women in the continuous estrogen-progestin combination group than the other groups and this difference was found to be statistically significant (P < 0.001). Breast density increase was observed in 18 of 30 women (60%) with higher doses of progestin compared to 5 of 30 women (16.7%) with lower dose (P < 0.05). CONCLUSIONS: Postmenopausal HRT may increase mammographic breast density. Breast density appears to be mostly affected by higher doses and continuous administration of progestin.     

Assessment of mammographic density in postmenopausal women during long term hormone replacement therapy

Abstract

Objective: To assess long-term effects of different hormone replacement therapy (HRT) regimens on mammographic density.

Methods: One hundred sixty-five postmenopausal women were treated with the same HRT during 5 years: 38 received transdermal estradiol, 78 cyclic combined therapy and 49 continuous combined therapy. Mammograms were obtained at baseline, at 1-year and 5-year treatment. Breast density changes were categorized as slight focal increased density, considerable focal increased density, slight diffuse increased density and considerable diffuse increased density.

Results: Mammographic density increased in 7.9% of women receiving estrogen alone versus 25.2% of women receiving combined therapy (p?<?0.022) during 1 year, and in 7.9% of women versus 28.3% of women (p?<?0.009) after 5 years of therapy, respectively. There were significant statistical differences in women treated with estrogen alone versus those treated with combined HRT after 1 and 5 years. After 5 years of HRT, breast density increased 21.8% in women receiving cyclic combined therapy versus 38.8% in those under continuous combined therapy (p?<?0.039).

Conclusion: An increase in breast density is significantly more frequent in women receiving combined estrogen-progestin therapy than in women receiving estrogen alone. There are differences between cyclic and continuous combined therapy at 5 years of treatment.     

Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women

OBJECTIVE: To compare changes in mammographic density and the expression of markers of proliferation (Ki67) and apoptosis (Bcl-2) after 1 year of treatment with tibolone and continuous conjugated equine estrogens combined with medroxyprogesterone acetate (CEE-MPA). DESIGN: Comparative, randomized, evaluator-blinded study. SETTING: City research hospital. PATIENT(S): Thirty-seven postmenopausal women. INTERVENTION(S): Tibolone (2.5 mg; n = 18) or continuous conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (5 mg; n = 19) for 1 year. MAIN OUTCOME MEASURE(S): Mammographic density (BI-RADS density score), expression of immunohistochemical markers Ki67 and Bcl-2. RESULT(S): Mean breast density score decreased significantly from 2.22 to 1.67 in the tibolone group, compared with a significant increase in the CEE-MPA-treated group from 1.84 to 2.63. Ki67 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 1 of 19, 15 of 19, and 3 of 19 subjects, respectively, in the CEE-MPA group. Bcl-2 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 5 of 19, 9 of 19, and 5 of 19 subjects, respectively, in the CEE-MPA group. CONCLUSION(S): One-year treatment with tibolone induced a decrease in breast density, with a reduction in proliferation and a stimulation of apoptosis, whereas 1-year treatment with CEE-MPA induced an increase in breast density, with stimulation of proliferation and inhibition of apoptosis, indicating that tibolone effects on the breast are different from those of CEE-MPA.     

The effects of oral estrogen-progestin compounds on blood coagulation factors

Oral contraceptives increase the levels of coagulation Factors II (prothrombin), VII (proconvertin), IX (plasma thromboplastin component), and X (Stewart factor) which form the prothrombin complex or vitamin-K-dependent factors. These factors occur in the progressive clotting process initiated by ruptured endothelium (intrinsic mechanism) or by tissue thromboplastin (extrinsic). Although Factors I (fibrinogen), VII, VIII (antihemophilic), IX, X, and platelets are increased in pregnancy, thromboembolism is more likely to occur in the postpartum period. During 1966-1967, 51 deaths and 183 nonfatal cases of thromboembolism among pill users were reported to the U.S. Food and Drug Administration. Several women known to have experienced a thromboembolism while using oral contraception had a second thromboembolic episode when the pill was resumed. In one of these women, coagulation factors were observed to rise during the second course of steroids when the second thromboembolism occurred. Further evidence associating thromboembolism and oral contraceptives comes from British case-controlled retrospective data and from studies with oral estrogens and progestins for menstrual indications. Research on animal models and screening tests is underway.     

Low-dose contraceptive estrogen-progestin and coronary artery atherosclerosis of monkeys

OBJECTIVE: To determine the separate and combined effects of the estrogen and progestin components of a modern triphasic oral contraceptive (OC) formulation on extent of coronary artery atherosclerosis. METHODS: Female cynomolgus monkeys (n = 81) were fed atherogenic diets for 32 months. After the first 7 months, they were randomized to four groups and treated triphasically for 21 of each 28 days with ethinyl estradiol (E2) (monkey equivalent of 30-40 microg), levonorgestrel (monkey equivalent of 50-125 microg), a combination of the two steroids, or placebo. RESULTS: Treatment with estrogen alone reduced coronary artery atherosclerosis extent 67% compared with untreated controls (P <.05). Treatment with progestin alone had no effect (P >.20). While atherosclerosis extent in monkeys treated with the combined OC was reduced 28%, this did not differ statistically from the other groups (P >.20). CONCLUSION: In doses used for oral contraception, E2, like all other estrogens studied to date, has a marked inhibitory effect on atherosclerosis progression. Levonorgestrel, at doses used in modern OC formulations, antagonizes this effect. When considered with other experimental evidence, these findings support the concept that progestins used in OCs and hormone replacement therapy can antagonize estrogen's atheroinhibitory effects. Whether this occurs seems to depend on a relative balance between estrogen and progestin with respect to dose, potency, route, and pattern of administration. However, when considered with evidence from previous studies, the findings also indicate a modest atheroinhibitory influence of combination (estrogen-progestin) OCs.