Estrogen

Laurie Barclay, MD

Aug. 7, 2003 — Transdermal estrogen therapy is not associated with an increased risk of venous thromboembolism (VTE), according to the results of a multicenter, case-control study published in the Aug. 9 issue of The Lancet.

"Oral but not transdermal estrogen replacement therapy (ERT) is associated with a risk of VTE in postmenopausal women," lead author Pierre Yves Scarabin, from INSERM in Paris, France, says in a news release. "These data suggest that transdermal ERT might be safer than oral ERT with respect to thrombotic risk."

From 1999 through 2002, the investigators recruited 155 women with a first documented episode of idiopathic VTE, including 92 with pulmonary embolism and 63 with deep venous thrombosis, and compared them with 381 controls matched for center, age, and time of recruitment.

At enrollment, 21% of women with VTE and 7% of controls were current users of oral ERT, whereas 19% of women with VTE and 24% of controls were current users of transdermal ERT. After adjustment for potential confounding variables, women using oral ERT were more than three times more likely to develop VTE than were transdermal ERT users (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.8 - 6.8) and nonusers of ERT (OR, 3.5; 95% CI, 1.8 - 6.8).

Study limitations include the bias inherent in observational studies and potential confounding by differential prescription of oral or transdermal ERT according to known risk factors. "Our findings could be important in assessment of the risk-benefit profile of ERT," the authors write. "The effects of transdermal ERT on health outcomes should be assessed in randomized trials."

INSERM, FRM, Besins International, Sanofi, Aventis, and Servier Institute helped support this study.

Lancet. 2003;362:428-432

Reviewed by Gary D. Vogin, MD

Am J Cardiol. 2002; 89(12A):12E-17E; discussion 17E-18E (ISSN: 0002-9149)

Mendelsohn ME
Tufts University School of Medicine, Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA.

Estrogen has direct and indirect effects on the cardiovascular system that are mediated by the estrogen receptors ER-alpha and ER-beta. The direct effects of estrogen occur through rapid nongenomic and longer-term genomic pathways. The rapid effects of estrogen are mediated by ERs and result in the activation of endothelial nitric oxide synthase, leading to arterial vasodilation. Longer-term effects involve changes in gene and protein expression, modulating the response to injury and atherosclerosis. Estrogen also indirectly influences serum lipoprotein and triglyceride profiles, and the expression of coagulant and fibrinolytic proteins. Advanced atherosclerosis and certain progestins, however, may attenuate some of the protective effects of estrogen

Climacteric. 2001; 4(3):228-34 (ISSN: 1369-7137)

Erenus M; Karako?? B; G??rler A
Marmara University School of Medicine, Obstetrics and Gynecology Department Menopause Unit, Istanbul, Turkey.

OBJECTIVE: To compare the effects of transdermal and oral hormone replacement therapy on compliance and serum lipoproteins.

DESIGN: A total of 159 naturally menopausal women who received either 0.05 mg transdermal estradiol twice weekly or 0.625 mg oral conjugated estrogen daily, with 2.5 mg oral medroxyprogesterone acetate daily, were retrospectively studied. Continuation with or drop-out from treatment regimens, side-effects and bleeding patterns were recorded during a 2-year follow-up period. Baseline, first-year and second-year serum lipoprotein levels were compared between the two groups.

RESULTS: Of the 100 women taking oral estrogen, 28 (28%) had dropped out whereas of the 59 women receiving transdermal estrogen, 17 (28.8%) had dropped out at the end of 2 years. The occurrence of bleeding episodes was the most common reason given for discontinuation in both treatment groups (52.9% in the transdermal group and 35.7% in the oral treatment group). The mean increase in high-density lipoprotein (HDL) level for the first year and second year was 10.2 +/- 3.2% and 31.4 +/- 2.8%, and 13.5 +/- 3.2% and 33.6 +/- 3.6% with oral treatment and transdermal therapy, respectively. The mean decrease in total cholesterol for the first year and second year was 2.9 +/- 1.9% and 14.7 +/- 1.6%, and 5.6 +/- 1.7% and 5.7 +/- 1.6% with oral and transdermal treatment, respectively. Likewise, the mean decrease in low-density lipoprotein (LDL) cholesterol for the first year and second year was 6.2 +/- 2.5% and 18 +/- 2.9%, and 7.9 +/- 3.0% and 15.9 +/- 5.2% with oral and transdermal treatment, respectively. There was no significant difference between groups in any of the lipid parameters. Transdermal treatment decreased triglyceride levels by 33.7 +/- 3.9%, whereas oral estrogen treatment increased triglycerides by 18.6 +/- 4.3% at the end of 2 years. This difference between the two groups was statistically significant (p < 0.0001).

CONCLUSION: Continuation of treatment was similarly high at the end of 2 years with both transdermal and oral estrogen treatment. Both treatments changed serum lipids favorably. Nevertheless, triglycerides were increased by oral estrogen but decreased by transdermal treatment at 2 years; this difference between the groups was significant.

JAMA. 1995; 273(3):199-208 (ISSN: 0098-7484)

OBJECTIVE--To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women.

DESIGN--A 3-year, multicenter, randomized, double-blind, placebo-controlled trial.

PARTICIPANTS--A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy.

INTERVENTION--Participants were randomly assigned in equal numbers to the following groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP), 200 mg/d for 12 d/mo.

PRIMARY ENDPOINTS--Four endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease: (1) high-density lipoprotein cholesterol (HDL-C), (2) systolic blood pressure, (3) serum insulin, and (4) fibrinogen.

ANALYSIS--Analyses presented are by intention to treat. P values for primary endpoints are adjusted for multiple comparisons; 95% confidence intervals around estimated effects were calculated without this adjustment.

RESULTS--Mean changes in HDL-C segregated treatment regimens into three statistically distinct groups: (1) placebo (decrease of 0.03 mmol/L [1.2 mg/dL]); (2) MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2 to 1.6 mg/dL]); and (3) CEE with cyclic MP (increase of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0.13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinogen than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active treatments were not significant. Systolic blood pressure increased and postchallenge insulin levels decreased during the trial, but neither varied significantly by treatment assignment. Compared with other active treatments, unopposed estrogen was associated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other adverse effect differed by treatment assignment or hysterectomy status.

CONCLUSIONS--Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on postchallenge insulin or blood pressure. Unopposed estrogen is the optimal regimen for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.

J Reprod Med. 2000; 45(3 Suppl):245-58 (ISSN: 0024-7758)

Wagner JD
Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA.

Progestogens are clearly useful to balance the proliferative effects of estrogens on the endometrium; however, some progestogens have been shown to attenuate the cardiovascular benefits of estrogen, and this has been the subject of considerable debate. Accumulating evidence confirms the deleterious effects of medroxyprogesterone acetate on estrogen's cardioprotective effects and provides new and compelling evidence that not all progestogens are alike in this regard. Maintaining estrogen's cardioprotective effects is strongly dependent upon the type of progestogen and route and method of administration. Numerous periclinical studies conducted on nonhuman primates and other models have demonstrated that certain progestogens, such as micronized progesterone, can be administered concurrently with estrogen replacement therapy, providing protection against endometrial hyperplasia without significantly affecting the beneficial effects of estrogen on lipid profiles, atherosclerosis and vascular reactivity.

Circulation. 1999; 100(7):717-22 (ISSN: 1524-4539)

Cushman M; Legault C; Barrett-Connor E; Stefanick ML; Kessler C; Judd HL; Sakkinen PA; Tracy RP
Departments of Medicine, and Biochemistry, University of Vermont, Burlington, VT 05446, USA. mcushman@salus.uvm.edu

BACKGROUND: Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events. In contrast, in a recent clinical trial of women with coronary disease, a subgroup analysis demonstrated increased risk during the early months of therapy. Because higher levels of inflammation factors predict vascular disease outcomes, the effect of hormones on these factors is of interest.

METHODS AND RESULTS: Four inflammation-sensitive factors, C-reactive protein, soluble E-selectin, von Willebrand factor antigen, and coagulation factor VIIIc were measured at baseline, 12, and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, a randomized, placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors. Compared with placebo, all 4 active preparations resulted in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin (P=0.0001). There were no effects of treatment on concentrations of von Willebrand factor or factor VIIIc. There were no differences in effects among treatment arms. Relative to placebo, when combining active treatment arms, final concentrations of C-reactive protein were 85% higher whereas E-selectin was 18% lower compared with baseline.

CONCLUSIONS: Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein. Such an effect may be related to adverse early effects of estrogen therapy. In contrast, hormones reduced the concentration of soluble E-selectin, and this might be considered an anti-inflammatory effect. Because PEPI was not designed to assess clinical endpoints, studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed.

Thromb Haemost. 2001; 85(4):619-25 (ISSN: 0340-6245)

Vehkavaara S; Silveira A; Hakala-Ala-Pietilä T; Virkamäki A; Hovatta O; Hamsten A; Taskinen MR; Yki-Järvinen H
Department of Medicine, University of Helsinki, Finland.

We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 microg), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations. Oral therapy increased the plasma concentrations of factor VII antigen (FVIIag) and activated factor VII (FVIIa), and the plasma concentration of the prothrombin activation marker prothrombin fragment 1+2 (F1+2). Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type plasminogen activator (tPA) antigen concentrations and PAI-1 activity, and increased D-dimer concentrations, suggesting increased fibrinolysis. The concentration of soluble E-selectin decreased and serum C-reactive protein (CRP) increased significantly in the oral but not in the transdermal or placebo groups. In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) concentrations decreased while high-density-lipoprotein (HDL) cholesterol, apolipoprotein AI and apolipoprotein All concentrations increased significantly. LDL particle size remained unchanged. In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters. These data demonstrate that oral estradiol does not have uniformly beneficial effects on cardiovascular risk markers and that the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed.

JAMA. 2002; 288(3):321-33 (ISSN: 0098-7484)

Rossouw JE; Anderson GL; Prentice RL; LaCroix AZ; Kooperberg C; Stefanick ML; Jackson RD; Beresford SA; Howard BV; Johnson KC; Kotchen JM; Ockene J;
Division of Women's Health Initiative, National Heart, Lung, and Blood Institute, 6705 Rockledge Dr, One Rockledge Ctr, Suite 300, Bethesda, MD 20817, USA.rossouw@nih.gov

CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.

OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).

MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

Maturitas. 2000; 36(3):217-22 (ISSN: 0378-5122)

Itoi H; Minakami H; Iwasaki R; Sato I
Department of Obstetrics and Gynecology, Jichi Medical School, Minamikawachi-machi, 329-04, Tochigi, Japan.

OBJECTIVE: We investigated the long-term effects of oral estriol (E(3)) on serum levels of total cholesterol (t-Cho), high-density lipoprotein cholesterol (HDL-Cho), low-density lipoprotein cholesterol (LDL-Cho), and triglycerides in early menopausal women.

METHODS: We studied 67 healthy early menopausal women who were treated for 48 months with 2.0 mg of E(3) plus 2.5 mg of medroxyprogesterone acetate daily (E(3) group, n=21), 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily (CE group, n=19), or 1.0 microg of 1alpha-hydroxyvitamin D(3) daily or 1.8 g of calcium lactate containing 250 mg of elemental calcium daily (control group, n=27). The serum levels of t-Cho, HDL-Cho, LDL-Cho, and triglycerides were evaluated at baseline and every 6 months.

RESULTS: After 48 months of treatment, the t-Cho decreased significantly by 4.3+/-2.1% (mean+/-SE) from baseline in the E(3) group, did not change in the CE group (-1.9+/-2.1%), and significantly increased (5.4+/-3.4%) in the control group. The HDL-Cho significantly increased in the CE group (10.7+/-2.4%), but not in the E(3) group (3.8+/-3.3%) or in the control group (-3.6+/-3. 0%). The LDL-Cho significantly decreased in the CE group (-11.4+/-4. 0%), did not change in the E(3) group (-5.2+/-3.6%), and significantly increased in the control group (11.8+/-6.3%). The triglyceride level decreased significantly in the E(3) group (-6. 7+/-4.9%), whereas it significantly increased in the CE group (17. 6+/-11.4%), and did not change in the control group (6.1+/-6.4%).

CONCLUSIONS: Oral E(3) prevented a postmenopausal rise in the t-Cho. Oral estriol did not induce the hypertriglyceridemia that was seen after treatment with conjugated estrogen. Oral E(3) may be a useful alternative therapy in women with hypertriglyceridemia and in women who are reluctant to continue conventional hormone replacement therapy because of uterine bleeding.

J Obstet Gynaecol Res. 1996; 22(3):259-65 (ISSN: 1341-8076)

Minaguchi H; Uemura T; Shirasu K; Sato A; Tsukikawa S; Ibuki Y; Mizunuma H; Aso T; Koyama T; Nozawa S; Ohta H; Ikeda T; Kusuhara K; Ochiai K; Kato J; Kinoshita T; Tanaka K; Minagawa Y; Kurabayashi T; Fukunaga M

Department of Obstetrics and Gynecology, Yokohama City University School of Medicine, Kanagawa, Japan.

OBJECTIVES: To assess the effects of oral estriol on the bone mineral density (BMD) and bone metabolism in postmenopausal women.

METHODS: Seventy-five natural postmenopausal women with a BMD of more than 10% below the peak bone density were treated for 50 weeks with 2 mg/day estriol (E3) cyclically and 0.8 g/day of calcium lactate continuously. BMDs at L2-L4 were measured by dual energy X-ray absorptiometry (DXA).

RESULTS: The BMD increased 1.79% (p < 0.01 vs. pretreatment) after 50 weeks, accompanied with decrease of biochemical markers of bone turnover. With regard to climacteric symptoms, Kupperman's menopausal index improved (p < 0.01 vs. pretreatment) after 5 weeks of treatment. As to the incidence of adverse events genital bleeding was observed in only 8.0% of the subjects. Endometrial histology and cytology showed neither abnormalities nor hyperplasia during and after the treatment.

CONCLUSIONS: Estriol prevented postmenopausal bone loss and improved climacteric symptoms effectively with low incidence of genital bleeding.

Scand J Prim Health Care. 1992; 10(2):139-42 (ISSN: 0281-3432)

Kirkengen AL; Andersen P; Gjersøe E; Johannessen GR; Johnsen N; Bodd E
Department of Medicine, Red Cross Clinic, Oslo, Norway.

A block randomized, double-blind, group-comparative, placebo-controlled study was conducted to assess the effect of oestriol on recurrent urinary tract infections in postmenopausal women. 40 women, median age 78 years (66-91), 20 in each group, were treated with oestriol three mg p.o. per day or corresponding placebo for four weeks, followed by one mg per day for eight weeks. The main response parameter was the number of urinary tract infections per week in the two treatment periods. Both oestriol and placebo reduced the number of infections per week significantly in both periods, compared with the pretreatment period. There was no difference between oestriol and placebo treatment in the first period. In the second period, however, oestriol treatment was significantly more effective than placebo (p = 0.05). Correspondingly, there was a significant difference between the two groups in the vaginal pH at the end of the study (p less than 0.05). We conclude that oestriol reduces recurrent urinary tract infections in postmenopausal women.

Ann N Y Acad Sci. 1994; 743:213-30; discussion 230-1 (ISSN: 0077-8923)

Sherwin BB
Department of Psychology, McGill University, Montreal, Quebec, Canada.

Sufficient evidence now exists to support the contention that estrogen influences cognitive functioning in women. Moreover, the data strongly suggest that estrogen exerts a specific and not a global effect on cognitive functions. Whereas estrogen enhances and/or maintains aspects of verbal memory, it is without effect, or possibly even has a negative influence on spatial memory. Indeed, there is some preliminary evidence that progesterone may enhance visual-spatial skills in women but this needs to be confirmed. Estrogen also exerts a positive effect on sexually dimorphic cognitive skills in which females typically excel such as verbal articulation and fine motor skills. While the weight of the evidence supports the above conclusion, findings across studies are not entirely consistent. Some of the methodological problems that weaken these studies include generalizing from one or two cognitive tasks to the entire realm of cognitive functions, neglecting to assay plasma levels of estradiol to confirm cycle phase or compliance with hormone administration and neglecting to consider the differential availability to the brain of the various estrogen preparations and the effects of different routes of administration. Although, for the most part, the menstrual cycle studies and the postmenopausal studies in healthy women show that estrogen maintains verbal memory, the effect size is modest. There is no reason to believe, for example, that verbal memory is truly impaired in women during phases of the menstrual cycle marked by low levels of estrogen. Nor are 45-year-old untreated, surgically menopausal women clinically impaired to any degree that affects their daily functioning in the real world. In both cases, however, decrements in performance occur reliably in the laboratory. This raises the issue, therefore, of the clinical meaningfulness of these findings. One way to address the clinical relevance of the relationship between estrogen and memory and thus, on cognitive functioning of the brain, is to examine what is known of estrogenic effects on other physiological systems where we already have substantial information. For example, the vast majority of women experience bone loss following the menopause and many develop osteopenia (bone density more than two standard deviations below mean peak bone mass levels) which is asymptomatic. Then, with advancing age, some women with osteopenia develop osteoporosis, predisposing them to fractures following minimal trauma. It has been estimated that 40 per cent of women who live to age 80 will develop spinal fractures and 33 per cent of women who live to age 90 will experience a hip fracture.