Vladimir Hanes

Effects of a New Hormone Therapy, Drospirenone and 17-β-Estradiol, in Postmenopausal Women With Hypertension

Drospirenone (DRSP), a progestin with antialdosterone activity, has been developed for hormone therapy in combination with 17-&bgr;-estradiol (E2) in postmenopausal women. We evaluated the antihypertensive efficacy and safety of various doses of DRSP and E2 and estradiol alone in postmenopausal women with hypertension using ambulatory and clinic blood pressure (BP) monitoring. This was a randomized, double-blind clinical trial of 3 doses of DRSP combined with estradiol, estradiol alone, and placebo in 750 postmenopausal women with stage 1 to 2 hypertension between 45 to 75 years. Ambulatory and clinic BPs, potassium, aldosterone, and lipid measurements and adverse events were evaluated in postmenopausal women with stages 1 to 2 hypertension during 8 weeks of double-blind therapy. DRSP and E2 induced dose-related reductions in the ambulatory and clinic systolic BP with physiological increases in serum aldosterone. Significant decreases in 24-hour systolic pressure were observed at doses of 2 and 3 mg of DRSP combined with estradiol but not by estradiol alone or 1 mg of DRSP with estradiol. There were no significant changes from baseline in potassium in any treatment group. Small, significant reductions in total and low-density lipoprotein cholesterol occurred on all of the active treatments, and serum triglycerides did not change. Adverse event rates were low and similar across treatment groups. In conclusion, these data show that DRSP combined with E2 significantly reduces BP in postmenopausal women with hypertension and did not induce significant increases in serum potassium. These characteristics may lead to a new benefit for this novel hormone therapy in postmenopausal women with hypertension.

Antihypertensive Effects of Drospirenone With 17β-Estradiol, a Novel Hormone Treatment in Postmenopausal Women With Stage 1 Hypertension

Background—Drospirenone (DRSP) is a novel progestin with antimineralocorticoid activity that has been developed for hormone therapy in combination with 17&bgr;-estradiol (E2) in postmenopausal women. In prior studies with DRSP in postmenopausal women that were focused on relief of menopausal symptoms, DRSP/E2 yielded significant reductions in blood pressure (BP). Methods and Results—The effects of 3 mg DRSP/1 mg E2 on clinic and 24-hour ambulatory BP as well as potassium homeostasis were evaluated in postmenopausal women with stage 1 hypertension (systolic, 140 to 159 and/or diastolic, 90 to 99 mm Hg) in a 12-week, multicenter, double-blind, randomized, placebo-controlled study. Clinic BPs were measured at baseline and at 2, 4, 6, 8, and 12 weeks of therapy, whereas potassium was measured at 2, 6, and 12 weeks of therapy. Ambulatory BP was performed in a substudy at baseline and at the end of the trial. In the intention-to-treat population of 213 women, the clinic BP was reduced significantly on DRSP/E2 (clinic BP, −14.1/−7.9 for DRSP/E2 versus −7.1/−4.3 mm Hg for placebo, P<0.0001). In the subgroup of 43 women with ambulatory BP monitoring, the 24-hour BP fell by −8.5/−4.2 mm Hg versus −1.8/−1.6 mm Hg on placebo (P=0.002/0.07). There were no significant changes from baseline in potassium levels or in the incidence of hyperkalemia (≥5.5 meq/L) on DRSP/E2 compared with placebo. Conclusions—Combination therapy with DRSP/E2 significantly lowered both clinic and 24-hour systolic BP in postmenopausal women with stage 1 systolic hypertension. This characteristic may lead to benefit for cardiovascular risk reduction in this population.

Efficacy and safety of flibanserin in postmenopausal women with hypoactive sexual desire disorder: results of the SNOWDROP trial

ObjectiveThis study aimed to assess the efficacy and safety of flibanserin, a serotonin receptor 1A agonist/serotonin receptor 2A antagonist, in postmenopausal women with hypoactive sexual desire disorder (HSDD). MethodsNaturally postmenopausal women with HSDD received flibanserin 100 mg once daily at bedtime (n = 468) or placebo (n = 481) for 24 weeks. Co–primary endpoints were changes from baseline to week 24 in the number of satisfying sexual events (SSEs) across 28 days and in the Female Sexual Function Index (FSFI) desire domain score. Secondary endpoints included change from baseline in Female Sexual Distress Scale—Revised (FSDS-R) Item 13 score (which assesses distress due to low sexual desire), FSDS-R total score, and FSFI total score. The Patient Benefit Evaluation was asked on treatment discontinuation. ResultsThere were significant improvements with flibanserin versus placebo in the mean (SE) changes in the number of SSEs (1.0 [0.1] vs 0.6 [0.1]), FSFI desire domain score (0.7 [0.1] vs 0.4 [0.1]), FSDS-R Item 13 score (−0.8 [0.1] vs −0.6 [0.1]), FSDS-R total score (−8.3 [0.6] vs −6.3 [0.6]), and FSFI total score (4.2 [0.4] vs 2.7 [0.4]; all P < 0.01). More women on flibanserin (37.6%) than women on placebo (28.0%) reported experiencing meaningful benefits from the study medication on treatment discontinuation. The most frequent adverse events associated with flibanserin were dizziness, somnolence, nausea, and headache. ConclusionsIn naturally postmenopausal women with HSDD, flibanserin, compared with placebo, has been associated with improvement in sexual desire, improvement in the number of SSEs, and reduced distress associated with low sexual desire, and is well tolerated.

Content Validity of the Female Sexual Function Index (FSFI) in Pre‐ and Postmenopausal Women with Hypoactive Sexual Desire Disorder

INTRODUCTION The Female Sexual Function Index (FSFI) has consistently been shown to have discriminant validity, test-retest reliability, and internal consistency as a measure of female sexual function. However, the content validity (relevance, clarity, comprehensiveness) of the instrument in women with hypoactive sexual desire disorder (HSDD) must also be established. AIM The aim of this study were to assess the content validity of the FSFI, specifically the FSFI desire domain, in pre- and postmenopausal women with HSDD. METHODS Two single-visit content validation studies were conducted in the United States. Eligible premenopausal (both studies) and postmenopausal (second study only) women with HSDD completed the FSFI followed by one-on-one, face-to-face cognitive debriefing interviews including open-ended questions to capture information on their perceptions of the instrument. Information on womens experiences of decreased sexual desire was also captured. MAIN OUTCOME MEASURES The main outcome measures of this study were the womens ratings of the clarity, ease of understanding, comprehensiveness, and relevance of the 19 items of the FSFI. RESULTS Interviews with 15 premenopausal women (first study), and 30 pre- and 31 postmenopausal women (second study), were analyzed. Across the whole sample, most women (80-100%) found every item of the FSFI clear and easy to understand. The majority (53-70%) felt that the FSFI captured all their feelings about decreased sexual desire and other sexual problems, and most (84-90%) indicated that additional questions were unnecessary. Most women in both studies (93-100%) reported that the two items comprising the FSFI desire domain were clear, easy to understand, and were relevant to them. The majority of women thought that a recall period of ≥7 days is most relevant for recall of their sexual desire. CONCLUSIONS These studies establish the content validity of the FSFI in pre- and postmenopausal women with HSDD, supporting the use of this instrument as a measure of sexual function in women with this condition.

Randomized, placebo-controlled trial of the effects of drospirenone-estradiol on blood pressure and potassium balance in hypertensive postmenopausal women receiving hydrochlorothiazide

Objective:Drospirenone (DRSP), a spironolactone analog with aldosterone antagonist activity, is a novel progestogen developed for use as hormone therapy in postmenopausal women in combination with 17&bgr;-estradiol (E2). DRSP/E2 lowers blood pressure when used alone in hypertensive postmenopausal women or when administered concomitantly with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. DRSP/E2 has not been studied in combination with the widely prescribed hydrochlorothiazide (HCTZ). We investigated the effects of 3 mg DRSP/1 mg E2 versus placebo on blood pressure and potassium balance when added to existing therapy with 25 mg HCTZ in postmenopausal women with established stage I hypertension. Design:This was a single-center, double-blind, randomized, placebo-controlled, two-treatment, two 4-week treatment period crossover study in 36 postmenopausal women with stage I hypertension maintained on 25 mg HCTZ. The endpoint was a change from baseline in systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring. Safety monitoring included serum potassium (mEq/L) and adverse events. Results:Mean systolic and diastolic blood pressures by 24-hour ambulatory blood pressure monitoring were reduced significantly, by −7.2 and −4.5 mm Hg, respectively, with DRSP/E2 as compared with placebo. The decrease in potassium with HCTZ was 0.2 mEq/L less with DRSP/E2 than placebo, suggesting a potassium-sparing effect. The most frequently observed adverse events with DRSP/E2 were vaginal bleeding and breast tenderness, which were attributable to the hormone therapy. Conclusions:DRSP/E2 substantially lowers systolic and diastolic blood pressure when added to existing antihypertensive therapy with HCTZ in hypertensive postmenopausal women. In addition, DRSP/E2 has a potassium-sparing effect that counteracts HCTZ-induced potassium loss.

Effect of ultra-low-dose transdermal estradiol on breast density in postmenopausal women

Objective:Women with higher mammographic breast density have increased risk for breast cancer, and there is some evidence that a change in breast density may be a marker for change in risk for breast cancer. The purpose of this study was to determine whether 2 years of treatment with ultra-low-dose transdermal estradiol results in a change in breast density. Design:The Ultra-Low-dose Transdermal Estradiol Assessment was a randomized, blinded, placebo-controlled trial of 2 years of treatment with unopposed ultra-low-dose (0.014 mg/d) transdermal estradiol for prevention of osteoporosis in 417 postmenopausal women with no history of breast cancer who had not had a hysterectomy. We obtained mammograms at baseline and after 1 and 2 years of treatment from 276 of the participants. Right craniocaudal views were analyzed at a central radiology facility by a trained clinician blinded to treatment group and order of acquisition. Contour analysis was performed to define dense areas versus fatty tissue. Between-group differences in mean change in percent breast density from baseline to 1 and to 2 years of follow-up were assessed using linear regression models adjusted for clinical site. Results:Participants were 66 ± 5 years old and 94% were white. The average percent breast density at baseline was 34%. There was no significant difference between treatment groups in change in percent breast density after 1 year (between-group difference, 0.1%; 95% confidence interval, −1.3% to 1.6%) or 2 years of treatment (0.8%; −0.6% to 2.1%). Conclusions:Two years of treatment with ultra-low-dose transdermal estradiol did not increase breast density.

Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years

Objective:To investigate the effect of ultralow-dose transdermal estradiol on postmenopausal symptoms and side effects in a cohort of largely asymptomatic postmenopausal women aged 60 to 80 years. Design:This secondary analysis used data from the UltraLow-dose Transdermal estRogen Assessment trial, a randomized, placebo-controlled, double-blind trial in postmenopausal women to determine the skeletal effects and safety of ultralow-dose transdermal estradiol. Four hundred seventeen postmenopausal women, aged 60 to 80 years, were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). Participants were queried at each clinic visit about postmenopausal symptoms and side effects purported to be associated with estrogen therapy using a standardized questionnaire. Results:At baseline, 16% of women reported hot flashes, 32% reported vaginal dryness, and 35% reported trouble sleeping. Women who received ultralow-dose estradiol were no more likely to report improvement of hot flashes, vaginal dryness, or sleep difficulties than those who received placebo. Treatment with ultralow-dose estradiol did not cause breast tenderness, uterine bleeding, or other symptoms often attributed to estrogen, but vaginal discharge was more common in women who received estradiol compared with those who received placebo. Conclusion:In this population of older, largely asymptomatic women, ultralow-dose transdermal estradiol did not improve postmenopausal symptoms and did not cause side effects other than vaginal discharge. Further study is needed to determine whether this dose of transdermal estradiol is effective in treating symptoms of postmenopause in younger, more symptomatic women.

The effect of ultralow-dose transdermal estradiol on sexual function in postmenopausal women

OBJECTIVE This study was undertaken to examine the effect of ultralow-dose transdermal estradiol on sexual function in postmenopausal women. STUDY DESIGN Analysis of data from a multicenter, randomized, double-blind, placebo-controlled trial of a 0.014 mg/day transdermal estradiol patch in 417 women aged 60 to 80 years. Sexual function was assessed by self-administered questionnaires at baseline and 4, 12, and 24 months. A linear effects model was used to assess treatment effects using data from all on-study assessments. RESULTS Women randomly assigned to estradiol had a 4.3 point greater improvement in the vaginal pain/dryness domain relative to placebo (95% CI = 0.3-8.4, P = .04). No significant differences in frequency of sexual activity or other sexual function domains (desire, satisfaction, problems, or orgasm) were observed between treatment groups (P > or = .10 for all). CONCLUSIONS Ultralow-dose estradiol resulted in modest improvement in sexual function related to vaginal pain and dryness, but not in other domains of sexual function.

Evaluation of the Sexual Desire Relationship Distress Scale (SDRDS) in Women with Hypoactive Sexual Desire Disorder

INTRODUCTION The Sexual Desire Relationship Distress Scale (SDRDS) was developed to address the need for a patient-reported outcome (PRO) measure of sexual distress associated with hypoactive sexual desire disorder (HSDD). The SDRDS is a 17-item PRO that includes items related to personal distress and distress related to relationship with partner. AIM The aim of this article was to evaluate the psychometric properties of the SDRDS among women with HSDD. METHODS Pre- and post-menopausal women with HSDD or with no sexual dysfunction completed the SDRDS, Sexual Activity Questions, Female Sexual Distress Scale-Revised (FSDS-R), and desire domain of the Female Sexual Function Index (FSFI) at baseline and 2 and 4 weeks later. MAIN OUTCOME MEASURES The main outcome measures of this article were item performance, internal consistency, test-retest reliability, construct validity, known groups validity, and responsiveness of the SDRDS. RESULTS Data from 260 women were analyzed: 101 in each of the pre- and post-menopausal HSDD groups and 29 in each of the pre- and post-menopausal control groups. No differences emerged between pre- and post-menopausal women. Least-squares mean (±standard errors [SE]) SDRDS score was higher in women with HSDD than in women with no sexual dysfunction (43.1 ± 0.9 vs. 6.1 ± 1.7; P < 0.0001), supporting known groups validity. Individual item scores correlated with total scores (r = 0.7-0.9; P < 0.0001). Internal consistency was high, with a Cronbachs alpha of 0.973 at baseline. Test-retest reliability was good, with an intraclass correlation coefficient of 0.89. SDRDS scores correlated strongly with other measures of sexual distress and sexual function including the FSDS-R and FSFI desire domain items. Preliminary analyses suggested that the SDRDS was sensitive to changes in clinical status. CONCLUSIONS The SDRDS provides a comprehensive and reliable assessment of distress due to decreased sexual desire in women with HSDD and may be a useful measure of treatment effects in clinical trials in women with this condition.

Pharmacokinetics and pharmacodynamics of drospirenone-estradiol combination hormone therapy product coadministered with hydrochlorothiazide in hypertensive postmenopausal women.

The effects of combination hormone therapy of drospirenone (DRSP), a novel progestin with antialdosterone properties, and 17β‐estradiol (E2) on hydrochlorothiazide (HCTZ) pharmacokinetics/pharmacodynamics versus placebo were investigated in a double‐blind, placebo‐controlled, crossover study. Thirty‐six postmenopausal women with stage 1 hypertension maintained on 25 mg of HCTZ once daily were randomized to receive either 3 mg of DRSP/1 mg of E2 or placebo once daily for 4 weeks. Plasma HCTZ, serum DRSP, E2, potassium, aldosterone, and plasma renin activity were determined at baseline and after 4 weeks. Results showed that the combination of DRSP/E2 plus 25 mg of HCTZ is safe and well tolerated in hypertensive postmenopausal women. The pharmacokinetics of HCTZ were not affected by coadministration of DRSP/E2. The geometric mean ratios and 90% confidence intervals ([HCTZ + DRSP/E2]/[HCTZ + placebo]) for HCTZ (a) area under the serum/plasma concentration‐time curve from 0 to 24 hours and (b) maximum plasma concentration were 101 (90.7, 112) and 103 (92.8, 115), respectively. In the HCTZ + DRSP/E2 group, serum potassium, aldosterone, and plasma renin activity all increased in a manner marginally consistent with a beneficial antialdosterone effect, counteracting the HCTZ‐induced potassium loss and lowering both systolic and diastolic blood pressure. No dose adjustment is required when DRSP/E2 is added to antihypertensive therapy with HCTZ in hypertensive postmenopausal women.