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This study evaluated safety and efficacy of esterified estrogens and methyltestosterone administered alone or in combination for the treatment of hot flashes in menopausal women. The 0.30-mg esterified estrogens and 0.30-mg methyltestosterone combination was the lowest effective dose, and our results are consistent with the known safety profile of estrogen and androgen combination products.

Hormone therapy (HT) is a class of medications widely prescribed to women in the Western world. Evidence from animal models and in vitro studies suggests that estrogen may protect against nigrostriatal system injury and increase dopamine synthesis, metabolism, and transport. Existing epidemiologic research indicates a possible reduced risk of Parkinson's disease (PD) associated with HT use. The objective of this study was to evaluate PD risk associated with specific HT formulations. Neurologist-confirmed cases and age-matched controls were identified from Group Health Cooperative (GHC) of Washington State. Final analysis included 137 female cases and 227 controls. Hormone therapy use was ascertained from the GHC pharmacy database, further classified as conjugated estrogens, esterified estrogens, and progestin. Ever use of HT formulation demonstrated a suggested elevated risk with esterified estrogen use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.0-9.8), and no risk associated with conjugated estrogen use (OR, 0.6; 95% CI, 0.6-1.3). Restricting this analysis to prescriptions that included progestin further elevated the risk associated with esterified estrogen use (OR, 6.9; 95% CI, 2.1-22.9); again, no risk was associated with conjugated estrogen use (OR, 1.7; 95% CI, 0.6-5.0). The findings from this study suggest an increase in PD risk associated with esterified estrogen use combined with progestin, and no risk associated with conjugated estrogen with progestin. These findings could have important implications for choice of HT in clinical practice.

Hormone therapy (HT) is a class of medications widely prescribed to women in the Western world. Evidence from animal models and in vitro studies suggests that estrogen may protect against nigrostriatal system injury and increase dopamine synthesis, metabolism, and transport. Existing epidemiologic research indicates a possible reduced risk of Parkinson's disease (PD) associated with HT use. The objective of this study was to evaluate PD risk associated with specific HT formulations. Neurologist-confirmed cases and age-matched controls were identified from Group Health Cooperative (GHC) of Washington State. Final analysis included 137 female cases and 227 controls. Hormone therapy use was ascertained from the GHC pharmacy database, further classified as conjugated estrogens, esterified estrogens, and progestin. Ever use of HT formulation demonstrated a suggested elevated risk with esterified estrogen use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.0-9.8), and no risk associated with conjugated estrogen use (OR, 0.6; 95% CI, 0.6-1.3). Restricting this analysis to prescriptions that included progestin further elevated the risk associated with esterified estrogen use (OR, 6.9; 95% CI, 2.1-22.9); again, no risk was associated with conjugated estrogen use (OR, 1.7; 95% CI, 0.6-5.0). The findings from this study suggest an increase in PD risk associated with esterified estrogen use combined with progestin, and no risk associated with conjugated estrogen with progestin. These findings could have important implications for choice of HT in clinical practice.

In postmenopausal women, oral hormone therapy (HT) is responsible for more than two venous thrombosis (VT) events per 1,000 person-years of treatment (Rossouw et al, 2002). Recent evidence supports a synergistic effect of smoking and oral contraceptives on the risk of VT (Pomp et al, 2008). Because HT has similar components as oral contraceptives – oestrogen progestogen, albeit in lower doses - smokers could represent a group in whom the VT risk associated with HT is considerably increased. Although no interaction between smoking and HT was found in the Women’s Health Initiative (WHI) clinical trial (Cushman et al, 2004), the small number of smoking VT cases and the selection of healthy participants in that trial may limit the validity and generalizability of this null finding. Our aim was to investigate the presence of this interaction in a large population-based study. Among participants of the Heart and Vascular Health Study (HVH), a case-control study of cardiovascular outcomes among Group Health Cooperative (GHC) members in Washington State (Smith et al, 2004), we identified all post-menopausal women who suffered a first deep-venous thrombosis (DVT) and/or pulmonary embolism (PE), from 1 January 1995 to 31 December 2009. We obtained data from more than 90% (n=1926), of whom >95% had positive diagnostic imaging test results. Women with no history of VT (n=5146) were selected from a pool of randomly-chosen HVH controls. We excluded subjects who smoked pipes/cigars (n=3), subjects with missing smoking data (n=26), users of oral contraceptives during menopause (=31) and users of oestrogen patches or oral progestogen without oestrogen (n=62). The use of HT was determined from the GHC pharmacy database, from which we assumed 80% compliance with prescribing instructions (Smith et al, 2004). Information on smoking status came from a telephone interview for 58% of subjects and from the medical record review otherwise, with an agreement of 92% when both were available (Kappa=0.85). Demographic characteristics, past medical history and details of the VT were abstracted from the entire GHC ambulatory medical record and the telephone interview. Logistic regression models evaluated the association between HT use and the risk of VT, adjusting for matching factors (age, index years, hypertension), body mass index (BMI), recent diagnoses of cancer (within 5 years before to 3 months after index) and recent hospitalizations (within 6 months before index). Effect modification by smoking status was assessed by adding a multiplicative interaction term. Missing values for BMI (1%) and recent hospitalization (16%) were multiply imputed with a multivariate normal regression model generating 20 imputations (Schafer, 1999). During the study period, 1926 cases suffered a DVT (n=949), a PE (n=690) or both (n=287). Mean age and BMI of cases were 71 years and 29.5 kg/m2. Among 5066 controls, 90% were White, 9.4% were current smokers and 25.1% were using oral HT (9.9% with progestogen, almost exclusively medroxyprogesterone acetate). More than 85% of oestrogen preparations were conjugated equine oestrogen or esterified oestrogens. The median duration of use of oral HT after enrollment in GHC was 8.6 years for cases and 10.2 years for controls. Overall, compared with non-users, women using oral HT had an increased risk of VT (odds ratio [OR] 1.35, 95% confidence interval [CI] 1.16–1.57). The smoking status of the participants did not significantly modify this association (Table I). The OR for VT associated with HT was 1.42 (95%CI 1.16–1.74) among never smokers and 1.60 (95%CI 1.00–2.62) among current smokers, with no significant difference between these (OR ratio: 1.13, 95%CI 0.68–1.90, p=0.55). Similarly, no interaction was found when comparing former with never smokers: ratio of ORs 0.84, 95%CI 0.61–1.14, p=0.29. Table I Association between hormone therapy and venous thrombosis, stratified by smoking status. We explored effect modification by dose, oestrogen type, progestogen use and smoking dose. In analyses restricting HT users to those taking the modal dose of oestrogen, the OR associated with HT was similar for both never and current smokers: 1.41 (95%CI 1.12–1.77) and 1.45 (95%CI 0.83–2.54), respectively (OR ratio 1.03, 95%CI 0.57–1.87). When oestrogen types were restricted to conjugated equine oestrogen, the ORs were not different between never and current smokers: OR 1.94 (95%CI 1.51–2.49) and OR 1.67 (95%CI 0.86–3.24), respectively, OR ratio 0.86 (0.43–1.74). Further, we found no interaction when stratifying HT use into unopposed and opposed HT and when stratifying current smoking into light and heavy smoking ( 20 cigarettes/day). Compared with never-smokers not using HT, we observed a 20% higher risk of VT in current smokers not using HT, a 40% higher risk of VT in never-smokers using the modal dose of HT and a 70% higher risk of VT in current smokers using HT (Table II). There was no suggestion of a material additive interaction between smoking and HT. Table II Individual and joint associations of current smoking and hormone therapy with venous thrombosis In this large, population-based, case-control study, smoking status was not found to modify the association between HT and VT. Smoking itself is a weak risk factor for incident VT (Blondon et al, 2013). Therefore, our results suggest that smoking is not an important factor for the development VT in users of oral HT, similarly to those of the WHI clinical trial (Cushman et al, 2004; Curb et al, 2006). Our findings contrast with the observed synergistic effect of smoking and OC on the risk of VT (Pomp et al, 2008). This difference may be explained by the much lower potency of oestrogen found in HT preparations than in OC preparations, if a true biological interaction between oestrogen and smoking exists. The increased risk of VT associated with oral HT in our data is not as strong as reported elsewhere (Sweetland et al, 2012). Reasons for this may include the use of esterified oestrogens (Smith et al, 2004), low oestrogen dose and the high proportion of prevalent users. Oral oestrogens also increase the incidence of stroke and coronary heart disease in postmenopausal women (Rossouw et al, 2007), and smoking increases the risk of arterial cardiovascular events more than that of VT (Braekkan et al, 2011). For these reasons, caution is needed when prescribing oral HT to current smokers. The strengths of our study include its population-based design, the ascertainment of VT events and the high-quality measures of HT use through pharmacy records. Its limitations include the low generalizability to non-White races and new HT users. In conclusion, our data do not support the hypothesis that smoking modifies the association between HT and the risk of VT.

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Background— Joint exposure to oral conjugated equine estrogen (CEE) and prothrombotic genetic variants factor II G20210A or factor V G1601A (Leiden) increase venous thrombotic risk 6- to 16-fold in postmenopausal women. Esterified estrogen (EE), an alternative estrogenic compound, appears not to be associated with increased risk and nothing is known about the joint risk with prothrombotic genetic variants. Methods and Results— We conducted a population-based, case-control study among postmenopausal women within a health maintenance organization. Subjects included 328 cases who sustained a first venous thrombosis and 1591 controls. Current hormone use was defined using electronic pharmacy records and variants FII G20210A and FV Leiden were genotyped using blood samples. FII and FV Leiden variants were associated with 2.1-fold and 3.7-fold increases in venous thrombotic risk, respectively. Overall, CEE use was associated with a 2.5-fold increase in risk compared with no hormone use, whereas EE use was not associated with a statistically increased risk. Compared with no hormone use and no variant, joint exposure to CEE and either prothrombotic variant was associated with an odds ratio (OR) of 9.1 (95% CI: 4.5 to 18.2), whereas joint exposure to EE and either variant was associated with an OR of 2.1 (0.6 to 6.8). When analyses were restricted to hormone users with either variant, CEE use was associated with an OR of 5.3 (1.3 to 21.7) compared with EE use. Conclusions— These findings need replication and suggest EE use is associated with less risk than CEE use especially among 5% to 10% of women who are carriers of a prothrombotic variant.

Objectives: Clinical trials have demonstrated that oral conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) increases venous thrombotic risk but this safety issue has not been investigated for other oral estrogens. Based on observational study findings that esterified estrogen (EE) was not associated with venous thrombotic risk whereas CEE was, we hypothesized that CEE users would be more resistant to activated protein C (APC), a prothrombotic phenotype, than EE users. Methods: We conducted an observational, cross-sectional study of postmenopausal women 30–89 years old who were controls in a case–control study of venous thrombosis. Use of CEE, EE, and MPA at the time of phlebotomy was determined using computerized pharmacy records. APC resistance was measured in plasma by the endogenous thrombin potential normalized APC sensitivity ratio. Adjusted mean APC resistance values were compared across estrogen type and CEE:EE ratios are presented. Results: There were 119 CEE and 92 EE users at the time of phlebotomy. Compared with EE users, CEE users had APC resistance measures that were 52% higher (1.52; 95% confidence intervals: 1.07–2.17) in adjusted analyses. Restricting to modal dose users (0.625 mg) and stratifying by MPA use did not materially change associations. Conclusions: CEE use was associated with higher levels of APC resistance when compared with EE use in postmenopausal women. These findings might provide an explanation for the higher risk of venous thromboembolism previously observed with CEE compared with EE use and, if replicated, may have safety implications for women when choosing an estrogen for symptom relief.

The pharmacokinetics and enterohepatic cycling of oestradiol have been studied after three oral, single-dose administrations of equimolar doses of oestradiol alone, oestradiol plus desogestrel and oestradiol valerate, in a 3-way cross-over mode in 18 healthy postmenopausal women. Oestradiol was readily absorbed and metabolized to oestrone, which reached much higher serum concentrations (140pgmL−1) than its parent compound (35pgmL−1). All three formulations had the same kinetic profile and were bioequivalent on testing. Noticeable first and second absorption phases were apparent from the oestradiol and oestrone serum concentration-time curves for all oestradiol formulations. The mean serum concentration-time curves of the metabolite oestrone (corrected for endogenous oestrone) showed a second maximum at approximately 25 h. By means of line feathering, serum concentration-time curves were constructed which belonged to the first, second and third phases of absorption. The maximum serum concentration, Cmax, of the second absorption or recirculation of oestrone was 20% that of the first, and the Cmax of the third circulation was 50% that of the second. The areas under the serum-concentration-time curves (AUC) for the second and third recirculations were similar—each comprised 12–13% of the total AUC. The oral clearance values of the recirculations were constant (590Lh−1). Enterohepatic recirculation of endogenous compounds is aimed at maintaining a steady-state serum concentration for immediate use and hydrolysis in the target organs. It is concluded that exogenously added oestradiol and its metabolites follow the recirculation pathways of the endogenous oestrogen pool.

Background: Clinical trials of conjugated equine estrogen (CEE) or estradiol vs placebo in postmenopausal women have found no effect or an elevated risk of myocardial infarction (MI) and stroke. The association of these end points with the use of esterified estrogen (EE) is unknown. Methods: We examined the risk of MI and stroke associated with current use of CEE, use of EE, or nonuse of hormones in a population-based case-control study in a health maintenance organization. Cases were all postmenopausal women with an incident MI (n = 1644) or stroke (n = 1080). Controls (n = 4205) consisted of a random sample of postmenopausal women without MI or stroke. Current use of postmenopausal hormones was assessed using a computerized pharmacy database. Results: There was no difference in risk of MI or stroke associated with current use of CEE or EE compared with nonuse or for current use of CEE compared with EE. In analyses restricted to hormone users, there was a suggestion of higher ischemic stroke risk associated with CEE alone (without progestin) compared with EE alone (odds ratio, 1.57; 95% confidence interval, 0.98-2.53). There was also a suggestion that when initiated in the previous 6 months, CEE was associated with a higher risk of MI than EE (odds ratio, 2.33; 95% confidence interval, 0.93-5.82). Conclusion: Further study may be warranted of the effects of EE on the risk of cardiovascular end points.

ContextClinical trial evidence indicates that estrogen therapy with or without progestins increases venous thrombotic risk. The findings from these trials, which used oral conjugated equine estrogens, may not be generalizable to other estrogen compounds.ObjectiveTo compare risk of venous thrombosis among esterified estrogen users, conjugated equine estrogen users, and nonusers.Design, Setting, and ParticipantsThis population-based, case-control study was conducted at a large health maintenance organization in Washington State. Cases were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first venous thrombosis between January 1995 and December 2001 and controls were matched on age, hypertension status, and calendar year.Main Outcome MeasureRisk of first venous thrombosis in relation to current use of esterified or conjugated equine estrogens, with or without concomitant progestin. Current use was defined as use at thrombotic event for cases and a comparable reference date for controls.ResultsFive hundred eighty-six incident venous thrombosis cases and 2268 controls were identified. Compared with women not currently using hormones, current users of esterified estrogen had no increase in venous thrombotic risk (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.69-1.22). In contrast, women currently taking conjugated equine estrogen had an elevated risk (OR, 1.65; 95% CI, 1.24-2.19). When analyses were restricted to estrogen users, current users of conjugated equine estrogen had a higher risk than current users of esterified estrogen (OR, 1.78; 95% CI, 1.11-2.84). Among conjugated equine estrogen users, increasing daily dose was associated with increased risk (trend P value = .02). Among all estrogen users, concomitant progestin use was associated with increased risk compared with use of estrogen alone (OR, 1.60; 95% CI, 1.13-2.26).ConclusionOur finding that conjugated equine estrogen but not esterified estrogen was associated with venous thrombotic risk needs to be replicated and may have implications for the choice of hormones in perimenopausal and postmenopausal women.