Gender-Affirming Hormone Therapy for Transgender Females.

The provision of hormone therapy, both estrogens and antiandrogens, to adult transgender females is well within the scope of practice of the obstetrician gynecologist. The goal is to induce feminizing changes and suppress previously developed masculinization. Estrogens in sufficient doses will usually achieve both goals with augmentation by antiandrogens. The primary short-term risk of estrogens is thrombosis, but long-term risk in transgender females is unclear. Optimal care requires pretreatment education and assessment, individualized dosing, ongoing routine monitoring, and standard breast and prostate cancer screening.

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.

Combined conjugated esterified estrogen plus methyltestosterone supplementation and risk of breast cancer in postmenopausal women.

OBJECTIVES: Testosterone supplementation is being prescribed increasingly to treat symptoms of hormone deficiency in pre- and postmenopausal women; however, studies of the association of testosterone therapy, alone or in combination with estrogen, with risk of breast cancer are limited. The current study assessed the association of combination conjugated esterified estrogen and methyltestosterone (CEE+MT) use and breast cancer risk in postmenopausal women in the Women's Health Initiative (WHI). STUDY DESIGN: At Year 3 of follow-up, women in the WHI observational study (N=71,964) provided information on CEE+MT use in the past two years, duration of use, and the brand name of the product. In addition, in each of years 4-8, women were asked whether they had used CEE+MT in the previous year. After 10 years of follow-up, 2832 incident breast cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of CEE+MT use (irrespective of use of other hormones) and of exclusive CEE+MT use in relation to breast cancer risk. RESULTS: Neither CEE+MT use nor exclusive use of CEE+MT was associated with risk: multivariable-adjusted HR 1.06, 95% CI 0.82-1.36 and HR 1.22, 95% CI 0.78-1.92, respectively. Among women with a natural menopause, the HR for exclusive use was 1.32 (95% CI 0.68-2.55). There was no indication of an association when repeated measures of CEE+MT use were included in a time-dependent covariates analysis. CONCLUSION: The present study, the largest prospective study to date, did not show a significant association of CEE+MT supplementation and risk of breast cancer.

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.

Schedules of controlled substances; exempt anabolic steroid products. Final rule.

The Drug Enforcement Administration (DEA) is finalizing an Interim Rule designating six pharmaceutical preparations as exempt anabolic steroid products under the Controlled Substances Act. This action is part of the ongoing implementation of the Anabolic Steroids Control Act of 1990.

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.

The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women.

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.

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.

Combined esterified estrogens and methyltestosterone versus esterified estrogens alone in the treatment of loss of sexual interest in surgically menopausal women.

OBJECTIVE: To compare the effect of esterified estrogens and methyltestosterone versus esterified estrogens alone on diminished sexual interest in surgically menopausal women. DESIGN: This randomized, double-blind study compared the effect of combined esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) (EE/MT) versus esterified estrogens (1.25 mg) alone (EE) for 8 weeks. Several different sexual function questionnaires were used to measure response to therapy. Changes from baseline in sexual interest/function and hormone levels were evaluated after 4 and 8 weeks of treatment. RESULTS: A total of 102 women were randomized into the study; 52 (age range, 32-61 years) to EE/MT and 50 (age range, 33-62 years) to EE. After 8 weeks, significant differences between treatments were not seen in the Changes in Sexual Functioning Questionnaire (CSFQ-F-C) sexual desire/interest subscale score, the primary efficacy variable. In contrast statistically significant between-treatment differences were found for several secondary efficacy variables including Menopausal Sexual Interest Questionnaire (MSIQ) sexual interest/desire score, CSFQ-F-C arousal/erection subscale score and Women's Health Questionnaire sexual functioning subscale score. The mean serum concentration of bioavailable and free testosterone significantly increased, approximately doubling between baseline and the end of the study in patients receiving EE/MT, with a significant (P < 0.001) between-treatment difference. The mean serum concentration of sex hormone-binding globulin significantly decreased to less than one third of the pretreatment levels in patients receiving EE/MT (P < 0.001). Both treatments were well tolerated. CONCLUSIONS: The mixed results seen with the different sexual function questionnaires may be due to the CSFQ-F-C's lack of specificity for this population. Increased levels of bioavailable and free testosterone paralleled the improved MSIQ item scores. Both the EE and EE/MT treatments were well tolerated.

Combined esterified estrogen and methyltestosterone treatment for dry eye syndrome in postmenopausal women.

PURPOSE: To determine whether systemic replacement with combined esterified estrogen (EE) and methyltestosterone (MT) (EE + MT) would reduce symptoms and promote clinical improvement in postmenopausal women with dry eye syndrome (DES). DESIGN: Retrospective, noncomparative, interventional case series. METHODS: Investigators reviewed the charts of 11 postmenopausal women treated within the last 3 years with EE + MT. RESULTS: The mean patient age was 65.2 years (standard deviation [SD] 11.4, range 48-84 years). The mean treatment duration was 12.2 months (SD 6.2 months, range 4-24 months). Ten (91%) of 11 patients reported improvement in dry eye symptoms while receiving treatment. For these 10, relief occurred after an average of 4.1 months of treatment (SD 3.2, range, 1-9 months). CONCLUSIONS: Treatment with EE + MT may be efficacious for DES of various etiologies. A randomized placebo-controlled trial is planned to further evaluate these encouraging findings.

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.

Effect of the combination of methyltestosterone and esterified estrogens compared with esterified estrogens alone on apolipoprotein CIII and other apolipoproteins in very low density, low density, and high density lipoproteins in surgically postmenopausal women.

Androgens are known to lower plasma triglycerides, an independent risk factor for coronary heart disease (CHD). Triglycerides are carried in plasma on very low density (VLDL) and low density (LDL) lipoprotein particles. Apolipoprotein CIII (apoCIII), a strong predictor of CHD, impairs the metabolism of VLDL and LDL, contributing to increased triglycerides. The objective of this study was to assess the effect of oral methyltestosterone (2.5 mg/d), added to esterified estrogens (1.25 mg/d), on concentrations of apolipoproteins and lipoproteins, specifically those containing apoCIII, compared with esterified estrogens alone in surgically postmenopausal women. The women in the methyltestosterone plus esterified estrogen group had significant decreases in total triglycerides, apoCI, apoCII, apoCIII, apoE, and high density lipoprotein (HDL) cholesterol compared with those in the esterified estrogen group. The decreases in apoCIII concentrations occurred in VLDL (62%; P = 0.02), LDL (35%; P = 0.001), and HDL (17%; P < 0.0001). There were also decreases in cholesterol and triglycerides concentrations of apoCIII containing LDL, and apoCI concentration of apoCIII containing VLDL. There was no effect on VLDL and LDL particles that did not contain apoCIII or on apoB concentrations. In conclusion, methyltestosterone, when administered to surgically postmenopausal women taking esterified estrogen, has a selective effect to reduce the apoCIII concentration in VLDL and LDL, a predictor of CHD. Methyltestosterone may lower plasma triglycerides through a reduction in apoCIII.

Estratest and Estratest HS (esterified estrogens and methyltestosterone) therapy: a summary of safety surveillance data, January 1989 to August 2002.

BACKGROUND: The use of hormone-replacement therapy (HRT) to treat menopausal symptoms has been influenced over the years by various safety concerns. These concerns include endometrial cancer, breast cancer, and cardiovascular disease, and have altered how HRT is prescribed. Evaluating postmarketing surveillance data for a product can help pharmaceutical manufactures and health care providers detect early safety signals that may call for further investigation of the product for safety risks. OBJECTIVE: This review summarizes the safety surveillance data for Estratest and Estratest HS from January 1989 to August 2002. METHODS: All adverse-event (AE) data reported to Solvay Pharmaceuticals, Inc., on this brand from January 1989 to August 2002 were accessed from a database system that uses a comprehensive software package for reporting and tracking clinical and postmarketing AEs. RESULTS: Exposure to the Estratest brand during the 13-year assessment period is estimated at >3.0 million patient-years. A total of 1372 unique case reports containing 2556 AEs were found. Assessment of the 43 (3.1%) serious AE cases reported did not generate any signals that might raise concern on the part of the medical community or consumers. Nonserious events comprising >4% of total AEs were all labeled events and included alopecia (8.8%), acne (5.6%), and hirsutism (4.5%). CONCLUSIONS: The relatively small number of serious AE reports compared with the significant patient exposure did not generate any signals that might raise concern on the part of the medical community or consumers. The safety profile suggests that continued use at the lowest effective dose is acceptable in menopausal women whose symptoms are not improved by estrogen alone.

Esterified estrogens combined with methyltestosterone improve emotional well-being in postmenopausal women with chest pain and normal coronary angiograms.

OBJECTIVE: The cardiac syndrome X is described as the triad of angina pectoris, a positive exercise test for myocardial ischemia, and angiographically smooth coronary arteries. Although syndrome X does not result in an increased risk of cardiovascular mortality, the symptoms are often troublesome and unresponsive to conventional antianginal therapy. The majority of patients are postmenopausal, and estrogen therapy can alleviate anginal symptoms. We investigated the effect of esterified estrogens combined with methyltestosterone (Estratest) on quality of life in postmenopausal women with syndrome X. DESIGN: Patients were withdrawn from antianginal therapy. Sublingual nitrates were allowed for treatment of anginal episodes. Patients underwent treadmill testing, and quality of life was assessed by using the Short Form-36 and Cardiac Health Profile questionnaires after the women had received 8 weeks of Estratest or identical placebo in a randomized, double-blind, cross-over study. RESULTS: Nineteen patients were randomized, and 16 patients completed the protocol. Plasma 17beta-estradiol concentrations were significantly increased by Estratest; however, total testosterone levels were not. The "emotional" score of the Cardiac Health Profile questionnaire was significantly improved after Estratest use compared with placebo (p = 0.03); however, there was no significant change in the Short Form-36 questionnaire for any variable. Estratest significantly increased systolic blood pressure and rate pressure product at rest but had no effect on exercise parameters. Time to onset of chest pain during exercise was also unaffected. CONCLUSIONS: We have demonstrated a beneficial effect of Estratest on emotional well-being in postmenopausal women with cardiological syndrome X. There was no significant treatment effect on exercise parameters, including time to onset of chest pain.