Formulations of hormone therapy and risk of Parkinson's disease.

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.

Safety and efficacy of low-dose esterified estrogens and methyltestosterone, alone or combined, for the treatment of hot flashes in menopausal women: a randomized, double-blind, placebo-controlled study.

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.

Postmenopausal estrogen-containing hormone therapy and the risk of breast cancer.

OBJECTIVE: To investigate the relation of various estrogen-containing hormone therapies to the risk of breast cancer, emphasizing the use of the combination of estrogen and testosterone. METHODS: Using information from a large U.S.-based claims database, we conducted a case-control study in women aged 50 to 64 years who had a first-time diagnosis of breast cancer to estimate the effect in users of conjugated estrogen alone, conjugated estrogen plus progestin, esterified estrogen with methyltestosterone, or esterified estrogen with methyltestosterone plus progestin, compared with nonusers. Four controls were matched to each case on year of birth and index date. Odds ratios (ORs) were calculated using conditional logistic regression. RESULTS: We identified 4,515 cases and 18,058 matched controls. The OR for users of estrogen alone compared with the nonusers was 0.96 (95% confidence interval [CI] 0.88-1.06; 667 cases and 2,900 controls); for users of conjugated estrogen plus progestin, it was 1.44 (95% CI 1.31-1.58; 712 cases and 2,087 controls); and for users of esterified estrogen with methyltestosterone and esterified estrogen with methyltestosterone plus progestin, the ORs were 1.08 (95% CI 0.86-1.36; 98 cases and 380 controls) and 1.69 (95% CI 1.03-2.79; 22 cases and 55 controls), respectively. There was an increased risk among conjugated estrogen plus progestin users of 48 months or more (OR 3.10, 95% CI 2.38- 4.04; 111 cases and 149 controls). CONCLUSION: There is no materially increased risk of breast cancer in users of estrogen alone or esterified estrogen with methyltestosterone compared with nonusers. There is an increased risk among those using conjugated estrogen plus progestin. In particular, the risk of breast cancer in women who used conjugated estrogen plus progestin for 4 or more years is approximately three times higher than in women who are not exposed to hormone therapy, so that the background incidence rate for women aged 50 to 64 years, which is around 3 per 1,000, would be increased to approximately 9 per 1,000 in women aged 50 to 64 years who have taken conjugated estrogen plus progestin for 48 months or more. LEVEL OF EVIDENCE: II.

Conjugated equine estrogen, esterified estrogen, prothrombotic variants, and the risk of venous thrombosis in postmenopausal women.

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.

Esterified estrogens combined with methyltestosterone raise intraocular pressure in postmenopausal women.

PURPOSE: To investigate the effect of esterified estrogens combined with methyltestosterone (EECM) (Estratest, Solvay, Pharmaceuticals, Inc, Baudette, Minnesota, USA) on intraocular pressure (IOP) in postmenopausal women. DESIGN: Observational case series. METHODS: The IOP of 13 consecutive postmenopausal women with dry eye syndrome were recorded before and during EECM therapy (1.25 mg of esterified estrogens and 2.5 mg of methyltestosterone for several months). RESULTS: The mean IOP increased from a baseline of 15.0 mm Hg before treatment to 18.2 mm Hg on EECM therapy (P < .0001) after a median duration of 11.3 months (range, 0.9 to 24 months). The increase in IOP was statistically significant at the 0.05 level of significance within three months and continued over 12 months. Two patients whose pressures increased (>4 mm Hg) returned to baseline levels after EECM was discontinued. CONCLUSIONS: Esterified estrogens combined with methyltestosterone produce a clinically significant increase in IOP in postmenopausal women with dry eye syndrome.

Esterified estrogen and conjugated equine estrogen and the risk of incident myocardial infarction and stroke.

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.

Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis.

CONTEXT: Clinical 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. OBJECTIVE: To compare risk of venous thrombosis among esterified estrogen users, conjugated equine estrogen users, and nonusers. DESIGN, SETTING, AND PARTICIPANTS: This 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 MEASURE: Risk 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. RESULTS: Five 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). CONCLUSION: Our 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.