By Archer, D F
Key words: HORMONE REPLACEMENT THERAPY, DROSPIRENONE, ESTROGEN, PROGESTIN, ESTRADIOL/DROSPIRENONE COMBINATION, MENOPAUSE
The efficacy of estrogen with or without a progestogen as hormone replacement therapy (HRT) for menopausal symptoms is well- established. Recent large-scale randomized studies with combined estrogen/progestogen therapy (EPT) have raised a number of safety issues, specifically the potential risk for coronary heart disease. Subsequent analyses and other studies have indicated that HRT may be cardioprotective in younger postmenopausal women. A new continuous EPT combines natural 17β-estradiol (E2) 1 mg with the novel progestin, drospirenone (DRSP) either 0.5 or 2 mg. DRSP has a physiological profile closer to that of natural progesterone than any other synthetic progestin. This paper reviews recent clinical trial data demonstrating the efficacy and safety of combined DRSP/ E2 therapy as EPT in postmenopausal women. DRSP/E2 provides symptomatic relief of vasomotor symptoms and improvement in genitourinary atrophy. DRSP/E2 protects against endometrial hyperplasia and reduces the risk of osteoporosis. Combined DRSP/E2 therapy has a favorable impact on cholesterol and triglyceride levels, and decreases blood pressure in women with elevated blood pressure. The favorable efficacy and safety profile of DRSP/E2, and potential for long-term health benefits, represents a new option for the effective management of menopause and its clinical sequelae.
The major benefits of hormone replacement therapy (HRT) include the relief of vasomotor symptoms, improvement of genitourinary atrophy and prevention of osteoporosis1,2. Perceived beneficial effects on lipid metabolism and cardiovascular function have also been reported3,4.
Nonetheless, despite the well-established efficacy of combined estrogen/progestogen therapy (EPT) in alleviating menopausal symptoms, there is also controversy regarding its safety5-7. EPT with synthetic progestins has been associated with serious adverse events, such as breast cancer, and unfavorable effects on metabolism and the cardiovascular system5,8,9. Subsequent analyses and further studies support a hypothesis that HRT may be cardioprotective in younger postmenopausal women10-12.
A new form of continuous combined EPT that contains naturally occurring 17β-estradiol (E2, 1 mg) and drospirenone (DRSP; 0.5 mg in the USA and 2 mg in the rest of the world) has recently become available (Angeliq; Schering AG, Berlin, Germany). DRSP is a unique progestin derived from spirolactone, and its pharmacological properties are more closely related to those of endogenous progesterone than any other synthetic progestogen13 . DRSP is an antimineralocorticoid steroid that has clinically relevant antialdosterone and antiandrogenic properties13-17. The combination of E2 and DRSP represents a potentially valuable therapeutic option for postmenopausal women. The purpose of the current article is to review pertinent data highlighting the safety and clinical utility of DRSP/E2, with particular focus on the results of a recent multicenter trial.
Figure 1 Endometrial thickness by treatment group (as measured by transvaginal ultrasound). Reproduced from Archer et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005;12:716-27, with permission from Lippincott Williams & Wilkins. DRSP, drospirenone; E2, 17β-estradiol
EFFICACY AND LONG-TERM SAFETY OF DROSPIRENONE/ ESTRADIOL
A multicenter, double-blind, randomized, parallel-group clinical trial of thirteen 28-day cycles of DRSP/E2 compared with E2 alone was conducted in postmenopausal women18. The primary endpoint was endometrial safety, as assessed by endometrial histology (biopsies performed at baseline, 7 months if indicated, and at the end of the study) and endometrial thickness using transvaginal ultrasound. Secondary endpoints included bleeding patterns, frequency and severity of hot flushes, urogenital symptoms, and health-related quality-of-life issues. Participants were required to have an intact uterus, amenorrhea of at least 12 months’ duration, an endometrial thickness of
A total of 1147 postmenopausal women were enrolled. Patients were randomized to receive either 1 mg E2 alone or 1 mg E2 plus 0.5, 1, 2, or 3 mg DRSP. Data related to the two currently available doses of DRSP (0.5 and 2 mg) were of particular interest. Patient demographics were comparable to those reported for postmenopausal women in other clinical trials.
Figure 2 Incidence of bleeding across all cycles and treatment groups18. DRSP, drospirenone; E2, 17β-estradiol
Endometrial hyperplasia was found in eight (4.6%) patients in the unopposed E2 group (p = 0.060), compared with one (0.7%) patient in the E2 plus 2 mg DRSP group (p = 0.007) by the end of the study protocol. There was no hyperplasia in the women receiving 0.5, 1.0 or 3.0 mg DRSP.
Endometrial thickness was not changed with combined DRSP/E2 treatment. There was a considerable increase in endometrial thickness by cycle 7 with E2 monotherapy. All DRSP groups showed a stable endometrial thickness by ultrasound throughout the study, with little difference between the treatment arms (Figure 1).
Some degree of endometrial bleeding and spotting is expected when postmenopausal women are treated with an estrogen and a progestin. All DRSP groups showed a slight increase in the frequency of endometrial bleeding after the first cycle of treatment in this study. The incidence of endometrial bleeding decreased during subsequent cycles in all treatment groups (Figure 2). It is interesting to note that women receiving E2 plus 2 mg DRSP demonstrated a lower incidence of bleeding than did those in the 0.5 mg DRSP group.
Treatment with E2 plus 0.5 or 2 mg DRSP also reduced total cholesterol, triglycride and lowdensity lipoprotein levels, though changes in high density lipoprotein and lipoprotein(a) were less marked (Table I)18. Furthermore, when compared with E2 monotherapy, the addition of 0.5 or 2 mg DRSP allowed patients to maintain or even lose weight compared with baseline (Figure 3). This effect may be attributable to DRSP’s antialdosterone effects, which counteract the sodium and water retention elicited by estrogens19-21. This observation may translate into higher rates of patient compliance as weight gain is a concern for many women receiving HRT22.
Urogenital symptoms improved in all treatment groups, with no significant differences between any of the DRSP arms. The frequency and severity of hot flushes were also reduced across all treatment groups by week 2 (p
Table 1 Mean changes in selected metabolic parameters from baseline to cycle 13 (absolute values). Columns in bold denote currently approved doses of drospirenone. Adapted from Archer et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005;12:716- 27, with permission from Lippincott Williams & Wilkins
Figure 3 Change in body weight with 17/?-estradiol (E2) and drospirenone (DRSP). Adapted from Archer et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double- blind, multicenter trial. Menopause 2005;12:716-27, with permission from Lippincott Williams & Wilkins
The results from this multicenter clinical trial18 suggest that DRSP/E2 combinations can improve health-related quality of life in postmenopausal women. The Women’s Health Questionnaire (WHQ) was administered at baseline and periodically throughout the study to evaluate a range of factors, including somatic symptoms, depressed mood, anxiety/fears, sexual functioning, sleep problems, cognitive difficulties, menstrual problems, attractiveness, and vasomotor symptoms. E2 plus 2 mg DRSP was significantly more effective than E2 alone in improving somatic symptoms (p = 0.034), and there was an overall positive mean change in the WHQ global score.
There was a small number of patients with breast pain, leukorrhea, and peripheral edema in all treatment groups. No serious adverse effects were observed in any patient. There was a low incidence of edema (in relation to body weight) in all DRSP treatment groups when compared with E2 therapy alone (Table 2)18.
Table 2 Selected adverse events by treatment group. Columns in bold denote currently approved doses of drospirenone. Adapted from Archer et al. Long-term safet\y of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005;12:716-27, with permission from Lippincott Williams & Wilkins
Table 3 Post-hoc analysis of blood pressure (BP, mmHg) in a subgroup of women with hypertension. Columns in bold denote currently approved doses of drospirenone. Adapted from Archer et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005;12:716- 27, with permission from Lippincott Williams & Wilkins
The impact of HRT on cardiovascular disease in postmenopausal women has been a major source of discussion and research for a long time. A post-hoc analysis of a subgroup of hypertensive women in this study found a significant reduction in blood pressure amongst women receiving DRSP in addition to E218. This effect was more marked for systolic blood pressure, though significant reductions in diastolic blood pressure were also observed by the end of the 13- month study (Table 3). These unique findings have paved the way for further trials investigating the blood pressure-lowering effects of combined DRSP/E2 therapy in postmenopausal women24-26.
DROSPIRENONE/ESTRADIOL REDUCES THE RISK OF OSTEOPOROSIS
Warming and colleagues27 recently reported the findings of a prospective, randomized, controlled study that evaluated the efficacy of combined DRSP/E2 in preventing postmenopausal osteoporosis. A total of 180 healthy postmenopausal women were randomized to receive placebo or 1 mg E2 combined with 1, 2, or 3 mg DRSP once daily for 2 years. Bone mineral density at the lumbar spine and hip was determined periodically during the study by dual X- ray energy absorptiometry.
Bone mineral density at both the lumbar spine and hip improved significantly in all women treated with combined DRSP/E2, regardless of the DRSP dose. By the end of the 2-year study, bone mineral density in treated patients had increased by approximately 7% and 4% in the lumbar spine and hip, respectively (all p
Figure 4 Effect of combined 17β-estradiol (E2)/drospirenone (DRSP) (2 mg) therapy on bone mineral density (BMD) in (a) the lumbar spine and (b) the hip. Adapted from Warming et al. Safety and efficacy of drospirenone used in a continuous combination with 17β-estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004;7:103-11, with permission from Taylor & Francis (http://www.tandf.co.uk/journals)
Data from recent clinical trials suggest that combined therapy with 1 mg E2 and 0.5 or 2 mg DRSP provides rapid and effective relief of menopausal symptoms, specifically hot flushes, and genitourinary atrophy18,23. The DRSP/E2 combination appears to enhance quality of life, with positive effects on anxiety, sexual function and cognition18. The antialdosterone properties of DRSP effectively counteract sodium and water retention; therefore women receiving DRSP avoid estrogen-related water retention and weight gain. Furthermore, 1 mg E2 combined with 2 mg DRSP has been shown to improve bone mineral density in postmenopausal women, thus reducing the risk of osteoporosis in this vulnerable population27.
Importantly, research to date shows that the currently available combinations of E2 ( 1 mg) and DRSP (0.5 or 2 mg) have good safety profiles, offering effective protection against endometrial hyperplasia and maintaining amenorrhea in the majority of women. The DRSP/E2 combination also demonstrated beneficial effects on the serum lipid profile in the prospective randomized clinical trial18. The post-hoc analysis of the participants with elevated blood pressure in this trial found that DRSP/E2 at all doses had a blood pressurelowering effect in hypertensive women18. These encouraging findings suggest that combined treatment with E2 and DRSP offers a new choice beyond the effective management of menopausal symptoms, with additional benefits due to its antialdosterone properties. DRSP presents an opportunity to re-evaluate the impact of the progestogen component of HRT28.
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D. F. Archer
CONRAD Clinical Research Center and Department of Obstetrics and Gynecology, Eastern Virginia
Medical School, Norfolk, Virginia, USA
Correspondence: Professor D. F. Archer CONRAD Clinical Research Center, 601 Colley Avenue, Norfolk Virginia 23507, USA
Conflict of interest Dr Archer is a consultant for, and has received honoraria from, Berlex Laboratories, Wyeth, Merck, Novo Nordisk, Ortho McNeil, Organon, Pfizer, Agile Therapeutics, Ascend Therapeutics, and Warner Chilcotte.
Source of funding Dr Archer has received grants from Berlex, Johnson and Johnson, Nov\o Nordisk, Wyeth, Organon, Solvay, and Warner Chilcotte.
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