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Therapeutic value and long-term safety of pulsed estrogen therapy
Maturitas 38 Suppl. 1 (2001) S23– S30 www.elsevier.com/locate/maturitas
Therapeutic value and long-term safety of pulsed estrogen therapy Martina Do¨ren a,*, Farook Al Azzawi b, Jacques Donnez c, Marius Jan Van der Mooren d, Jose´ Villero e, Anne Gompel f a
Free Uni6ersity of Berlin, Benjamin Franklin Uni6ersity Hospital, Clinical Research Center of Women’s Health, Berlin, Germany b Leicester Uni6ersity School of Medicine, Leicester, UK c Catholic Uni6ersity of Lou6ain, Brussels, Belgium d Department of Obstetrics and Gynaecology, Uni6ersity Hospital Vrije Uni6ersiteit, Amsterdam, The Netherlands e Hospital Reina Sofı´a, Co´rdoba, Spain f Department of Obstetrics and Gynaecology, Hoˆtel Dieu Hospital, Paris, France
Abstract Objecti6es: To demonstrate equivalent efficacy for menopausal symptoms between Aerodiol® nasal spray and reference oral estradiol therapy, and to investigate the endometrial safety and tolerability of Aerodiol in the long term. Methods: The efficacy of Aerodiol 300 mg, once daily, was compared with oral estradiol 2 mg/day in a randomized, double-blind trial. A statistical test of noninferiority was performed on the mean absolute Kupperman index (KI) obtained after 14 and 23 weeks of the two treatments. Long-term safety was assessed in a 1-year open-label study. The initial Aerodiol dose was 300 mg/day, and was adjusted if required. Endometrial biopsies were obtained at inclusion and at the end of the trial and examined independently by two pathologists. Results: In the equivalence trial, the KI improved similarly in the Aerodiol group (n= 317) and the oral estradiol group (n= 342). Aerodiol was shown statistically to be at least as effective as oral therapy (PB 0.001), but the incidences of mastalgia and withdrawal bleeding were significantly lower in the Aerodiol group (P B0.01 and P B 0.001, respectively). In the long-term safety trial (n= 408), the rate of Aerodiol treatment continuation at 12 months was 85%, and there was no incidence of endometrial hyperplasia or cancer. Aerodiol dose adaptation was performed by 29% of women. Conclusions: Aerodiol was shown to have equivalent efficacy to reference oral estradiol therapy, but with better gynaecological acceptability. The endometrial safety of Aerodiol was confirmed in the long term, and the ability to adjust the dosage easily was of benefit to a substantial proportion of women. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pulsed estrogen therapy; Estradiol nasal spray; Menopausal symptoms; Endometrial safety; Withdrawal bleeding
1. Introduction * Corresponding author. Tel.: + 49-30-84415811; fax: + 4930-84415819. E-mail address: [email protected] (M. Do¨ren).
Estrogen replacement therapy has been shown to be effective in reducing the vasomotor and urogenital symptoms of the menopause [1–3].
0378-5122/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0378-5122(01)00201-8
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Long-term estrogen supplementation is also effective in reducing the risk of low-trauma fractures due to postmenopausal bone loss [4,5] and the risk of cardiovascular disease [6]. The two most commonly used methods for the administration of estrogen supplementation are the oral and transdermal routes, but both have disadvantages. Oral estrogen is subject to substantial intestinal and hepatic first-pass metabolism [7,8], necessitating relatively high doses associated with high inter- and intraindividual variability and increased risk of gallbladder disease [9]. Transdermal administration, on the other hand, is associated with variable absorption rates between women [10], local skin irritation [11], and the loss of patches in 4– 8% of cases due to poor adhesion [12]. Aerodiol® is an aqueous solution of the natural 17b-estradiol delivered by a metered pump for intranasal administration, which represents a new approach to the treatment of menopausal symptoms. Aerodiol introduces the new concept of pulsed estrogen therapy. After nasal administration, plasma estradiol levels rise rapidly and fall to 10% of their peak level within approximately 2 h [13], unlike both oral and transdermal administration which produce prolonged or plateau estrogen elevations [14]. The efficacy of pulsed estrogen therapy in reducing postmenopausal symptoms has been demonstrated in a randomized, placebo-controlled trial [15], and 300 mg/day was identified as an appropriate initial dose. That trial also established the safety and tolerability of Aerodiol over a 12-week study period. However, the full benefits of estrogen supplementation require long-term therapy, so studies over a longer period of time are required. This paper describes studies performed with three main aims. The first aim was to demonstrate the equivalent efficacy of Aerodiol 300 mg/ day relative to a standard oral estradiol therapy of 2 mg/day. The second was to investigate the endometrial safety and tolerability of Aerodiol over a 1-year period. The third aim was to assess the therapeutic value of the potential benefits of Aerodiol, in terms of its general safety and the ease with which the dose can be adapted to suit individual needs.
2. Clinical efficacy of Aerodiol
2.1. Study design The equivalence of efficacy of Aerodiol 300 mg once daily to a standard dose of 2 mg/day of oral micronized estradiol was assessed in a randomized, double-blind, two-arm, parallel-group trial conducted in nine European countries [16]. Postmenopausal Caucasian women with moderate-tosevere menopausal symptoms, defined as a Kupperman index (KI) ] 15, were recruited to the trial. Women received either intranasal Aerodiol 300 mg (one spray in each nostril) plus an oral placebo capsule, or an oral estradiol 2 mg capsule plus placebo intranasal spray, every morning for 24 weeks. All women also received dydrogesterone 10 mg per day for 14 days per 28-day cycle. After 14 weeks’ therapy, the number of nasal sprays could be adjusted if there was evidence of over- or underdosage. The primary efficacy end point was the KI score after 14 weeks; the KI was also assessed at 23 weeks. The KI is a weighted evaluation of the incidence and severity of 11 of the most frequent menopausal symptoms, and has been extensively validated [1,17]. Of the symptoms included, hot flushes, night sweats, sleep disorders, and nervousness are weighted more heavily than depression, dizziness, tiredness, arthralgia, headache, palpitations, and vaginal dryness in the calculation of the index. In comparing KI scores between the two treatments, an equivalence limit of 9 4 points was set. This limit was determined before the start of the study by a scientific committee that included both statisticians and gynecologists specialized in hormone replacement therapy (HRT), and represents less than half the expected difference from placebo [18]. A one-tailed Student’s t-test was performed as a statistical test of noninferiority on the absolute mean KI scores; a significant result indicates that Aerodiol is at least as effective as the reference drug. The secondary efficacy end point was the number of hot flushes per day, which was assessed at weeks 14 and 23. Vaginal smears were taken at selection and at week 14, and endometrial samples were obtained at selection and at week 23. Bleeding patterns and
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the occurrence of genitourinary symptoms were recorded. Nasal tolerability was assessed in all women at week 14 and 23, and a subset of 199 women were examined by an ear, nose, and throat specialist before therapy and at week 23.
2.2. Results A total of 659 women were included and randomized. There were no differences in baseline characteristics between the groups (Table 1) and 559 women (85%) completed the trial. The majority of discontinuations were due to adverse events (28 in the intranasal group and 36 in the oral group). Compliance was extremely high (99% for the intranasal and 98% for the oral group at week 14). Adaptation of the number of sprays taken per day was required for 20% of women in the oral group and 22% in the intranasal group at week 14. After 14 weeks, the KI had decreased by a similar amount in both groups (Fig. 1). The difference between the mean KIs was 1.1, with a 90% confidence interval of 0.0– 2.2. The upper confidence limit was less than the predefined equivalence limit of + 4 points, indicating that Aerodiol 300 mg/day was at least as effective as oral estradiol 2 mg/day (P B0.001). Similar results were obtained after 23 weeks. Moreover, Aerodiol was also shown to be at least as effective as oral Table 1 Baseline demographic and clinical parameters of women in the clinical efficacy triala
Number of women Age (years) BMI (kg/m2) Age at menopause (years) Time since menopause (months) Previous hormone replacement therapy number (%) Daily incidence of hot flushesb a b
Aerodiol
Oral estradiol
317 51.0 9 4.2 25.19 3.9 48.29 4.2 39.19 33.8
342 51.2 9 4.2 25.3 94.2 48.8 9 4.1 35.4 933.7
134 (42)
145 (42)
6.19 3.7
6.4 94.4
Data are presented as mean 9S.D. unless indicated. During the preceding week.
Fig. 1. Mean KI ( 9S.D.) at baseline, week 14, and week 23 in women receiving Aerodiol 300 mg/day or oral micronized estradiol 2 mg/day.
therapy in two subgroups of women, those who had experienced more than seven hot flushes per day at baseline (P=0.01), and those who were smokers (\10 cigarettes per day; PB 0.001). Women in both the intranasal and oral therapy groups showed substantial and similar decreases in the incidence of hot flushes (Fig. 2). In both groups, the median incidence of hot flushes at week 14 and week 23 was zero. There were no significant differences between the intranasal and oral therapy groups in the frequency of genitourinary symptoms. The proportion of women with atrophic vaginal mucosa decreased from 28 and 29% at baseline to 1% in both treatment groups after 14 weeks. Improvement in the karyopyknotic index occurred in 90% of the Aerodiol group and 92% of the oral estradiol group.
2.3. Safety, tolerability, and acceptability The incidence of mastalgia was significantly lower in the Aerodiol group at both week 14 and 23. Moderate-to-severe mastalgia was reported in
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10% of women in the Aerodiol group and 16.5% in the oral estradiol group (P B 0.05). Five women prematurely stopped treatment due to mastalgia in the oral group, compared with none in the Aerodiol group (P B0.05). Significantly more women receiving oral therapy (69%) experienced withdrawal bleeding in all cycles than those receiving intranasal Aerodiol (49%), and the bleeding was of longer duration. No women in either group showed endometrial hyperplasia at baseline or after 23 weeks of study therapy. The rate of ‘atrophic’ endometrium was higher in the Aerodiol group (25%) than in the oral group (14%; Fig. 3). Thus pulsed estrogen therapy produced less stimulation of reproductive organs, such as the breast and endometrium, than oral therapy. Both therapies were well tolerated. There were only two serious adverse events related to the study therapy (one case of hematometra in each group). The incidence of adverse events was very similar in both groups; those related to treatment were of mild or moderate intensity in 95% of cases for the intranasal group and 90% for the oral
Fig. 2. Mean incidence of hot flushes ( 9 S.D.) at baseline, week 14, and week 23 in women receiving Aerodiol 300 mg/day or oral micronized estradiol 2 mg/day.
group. Nasal symptoms, including sneezing, itching, and rhinorrhea, were more frequent in the intranasal group, but only 1% of women in each group discontinued therapy prematurely as a result of local events. The acceptability of the nasal spray was recorded as good or excellent by 93 and 92% of women in the intranasal and oral therapy groups, respectively. Endometrial safety is an important issue with all forms of HRT, and is often a major concern for both the woman and the doctor. Although the results of this study indicated that Aerodiol induced less endometrial proliferation than oral estradiol of equivalent efficacy, it was important to investigate the endometrial safety and general acceptability of Aerodiol thoroughly over a longer period.
3. Long-term endometrial safety and tolerability
3.1. Study design The long-term endometrial safety and tolerability of Aerodiol was assessed over a 1-year period in an open-label, community-based, multicenter trial [19]. Postmenopausal, nonhysterectomized women who had completed a previous controlled study of Aerodiol and who wished to continue intranasal estradiol therapy for at least 1 year were recruited in six European countries. There was no mandatory washout period before entry and women could have received previously either different doses of nasal estradiol (from 100 to 900 mg/day) or placebo or micronized estradiol (1 or 2 mg) [15,16]. Initially, the women received Aerodiol 300 mg/ day as one spray of 150 mg in each nostril, either continuously or for 21–25 days/month. Dose adjustments were allowed at 3-monthly intervals if there were symptoms of under- or overdosage. Progestogen therapy was given for at least 12–14 days of each treatment cycle, as either a continuous or sequential regimen. A choice of five different progestogen therapies was available. Endometrial biopsies were obtained at study inclusion and after 12 months’ therapy. The histological material was assessed independently by
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Fig. 3. Classification of endometrial biopsies taken at week 23 in women receiving Aerodiol 300 mg/day (n =118) or oral micronized estradiol 2 mg/day (n = 114). No tissue indicates that the sample obtained was insufficient for histological analysis.
two pathologists who were blind to the therapy regimen. A consensus position was reached in all cases of disagreement. Cyclical and unexpected bleeding was assessed at quarterly interviews, at which any adverse events were also recorded.
3.2. Results A total of 408 women were recruited and 349 completed the study. Their mean age was 52.5 ( 9 3.9) years with body mass index (BMI) at 23.9 ( 9 3.4) and they had been menopaused for 3.2 ( 92.2) years. During the 1-year study period, 29% of women had their dose of Aerodiol increased or decreased at least once, by changing the number of sprays taken per day. The distributions of Aerodiol daily dosages during the first and last 3-month periods of the study are shown in Fig. 4. These distributions confirm that 300 mg/day is an appropriate dose both for initial and
long-term intranasal estradiol therapy. However, the ability to adjust the dose simply was a useful property for a substantial minority of women. Endometrial biopsies were available from 367 women at inclusion (M0) and 311 women after 12 months’ therapy (M12). Importantly, at M12 there was no incidence of cancer or endometrial hyperplasia (95% CI= 0–1.12), and the endometrium was mainly atrophic (34%) or secretory (39%). Only 2.8% of samples taken during the progestational phase were classified as proliferative. Biopsies were not taken at M12 for 38 women, because of either a narrow cervix or the woman’s refusal. For these women, vaginal ultrasound examination was used to rule out a significant endometrial abnormality. At quarterly interviews, cyclical bleeding was reported in 79–81% of sequential treatment cycles. Cyclical bleeding was of mild-to-average intensity in 92% of cycles at M3 and 98% of cycles at M12. Unexpected bleeding occurred in 15% of
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cycles with continuous therapy and in 4% of cycles with sequential cyclical therapy. Some 80% of unexpected bleeds were only spotting, and unexpected bleeding did not lead to premature treatment discontinuation in any women. One woman withdrew as a result of menorrhagia.
3.3. Tolerability and acceptability Aerodiol therapy was well tolerated, the rate of continuation of treatment at 12 months was 85%. This rate compares very favorably with that described in recent published studies of HRT administered by other routes [20– 23]. The most frequent adverse events were nasal symptoms, of which most were mild in intensity. Nasal events led to premature discontinuation of treatment in 14 (3.4%) women (nine for sneezing, three for nose itching, two for nose bleeding). All nasal events resolved spontaneously after discontinuation of treatment. Severe mastalgia was reported by 1.5% of women, and in one case led to premature withdrawal from treatment.
4. Comments The double-blind, double-dummy randomized trial described in this paper has established equivalent efficacy in the relief of menopausal symptoms between Aerodiol 300 mg/day and a widely used reference oral estrogen supplementation therapy, oral micronized estradiol 2 mg/day. This result was obtained for the study population as a whole, and for subpopulations of smokers and those with more severe menopausal symptoms at baseline. An important further result is that Aerodiol therapy demonstrated a lower stimulation of reproductive tissues (endometrium, breast) compared with the equivalent oral therapy. In addition, the long-term endometrial safety and tolerability of Aerodiol therapy were confirmed over a longer, 1-year study period. It had been suggested previously that Aerodiol 300 mg/day had a similar effect on the KI and the incidence of hot flushes as oral estradiol valerate 2 mg/day [15]. In the present study, the therapeutic equivalence of these two treatments with regard to
Fig. 4. Distribution of Aerodiol daily doses during the first (M0 – M3) and last (M9 – M12) 3-month period of the 1-year study.
M. Do¨ ren et al. / Maturitas 38 Suppl. 1 (2001) S23– S30
menopausal symptoms has been demonstrated formally, using a statistical test of noninferiority [18]. The improvements in the KI and the reductions in the incidence of hot flushes observed in the present study are similar to those reported previously for studies of oral and transdermal estrogen supplementation [24,25,27]. A previous placebo-controlled, dose-ranging study [15] identified 300 mg/day as an appropriate dose for initiating therapy with Aerodiol. The present studies have confirmed this and indicated that 300 mg/day is a satisfactory dose in the longer-term for the majority of women. However, the ability to adjust the dose of Aerodiol simply, without changing the dispenser, by increasing or decreasing the number of sprays taken per day was an important facility for a substantial minority of women. Pulsed estrogen therapy resulted in lower incidences of mastalgia and withdrawal bleeding than oral therapy over the 23-week study period, and this good gynecological acceptability was confirmed over 1 year. Intranasal therapy also showed a lower tendency to stimulate endometrial proliferation than the oral route, with a high incidence of atrophic endometrium maintained during the long-term study. Endometrial hyperplasia has an estimated incidence of 1– 2% after 1 year of combined HRT [28 –30]. No cases of endometrial hyperplasia or cancer were observed in either of the studies reported here involving more than 400 women. The reduced level of stimulation of the reproductive organs produced by Aerodiol compared with oral estradiol therapy of equivalent efficacy on climacteric symptoms may be related to the pulsed kinetic profile of estradiol exposure that occurs with the intranasal route [13]. The high level of gynecological acceptability of Aerodiol should encourage good compliance with therapy [31]. The intranasal route of administration was well tolerated. No new or additional nasal symptoms became apparent in these longer-term trials compared with previous studies of shorter duration [15–32]. The withdrawal rate due to local events compares favorably with that reported in a study of estrogen therapy by the transdermal patch [11]. The rate of treatment continuation that we ob-
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served after 1 year of therapy is high compared with some other published studies of HRT [20– 23]. Rates of continuation of HRT in the general population have recently been reported to be as low as approximately 33% [23] and less than 50% [21]. The present studies confirm that pulsed estrogen therapy provided by Aerodiol, in combination with continuous or sequential progestogen therapy, represents an effective, safe, well-tolerated, and highly acceptable form of HRT.
References [1] Kupperman KI, Blatt MHG, Wiesbader H, Filler W. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrheal indices. J Clin Endocrinol 1953;13:688 – 703. [2] Belchetz PE. Hormonal treatment of postmenopausal women. New Engl J Med 1994;330:1062 – 71. [3] Greendale GA, Lee NP, Arriola ER. The menopause. Lancet 1999;353:571 –80. [4] Christiansen GA, Christensen MS, McNair P, Hagen C, Stocklund KE, Transbol I. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Eur J Clin Invest 1980;10:273 – 9. [5] Michaelsson K, Baron JA, Farahmand BY, et al. Hormone replacement therapy and risk of hip fracture: population based case-control study. The Swedish Hip Fracture Study Group. Br Med J 1998;316:1858 – 63. [6] Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. New Engl J Med 1996;335:453 – 61. [7] De Lignieres B, Basdevant A, Thomas G, et al. Biological effects of estradiol-17b in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab 1986;62:536 – 41. [8] O’Connell MB. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol 1995;35(Suppl.):18S – 24S. [9] Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal hormone use and cholecystectomy in a large prospective study. Obstet Gynecol 1994;83:5 – 11. [10] Stanczyk FZ, Shoupe D, Nunez V, Macias-Gonzales P, Vijod MA, Lobo RA. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gynecol 1988;159:1540 – 6. [11] Frenkel Y, Kopernik G, Lazer S, et al. Acceptability and skin reactions to transdermal estrogen replacement therapy in relation to climate. Maturitas 1994;20:31 – 6. [12] The Transdermal HRT Investigators Group. A randomized study to compare the effectiveness, tolerability and
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M. Do¨ ren et al. / Maturitas 38 Suppl. 1 (2001) S23– S30 acceptability of two different transdermal estradiol replacement therapies. Int J Fertil Menopausal Stud 1993;38:5 – 11. Devissaguet JP, Brion N, Lhote O, Deloffre P. Pulsed estrogen therapy: pharmacokinetics of intranasal 17bestradiol (S 21400) in postmenopausal women and comparison with oral and transdermal formulations. Eur J Drug Metab Pharmacokinet 1999;24:265 –71. Scott RT, Ross B, Anderson C, Archer DF. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol 1991;77:758 –64. Studd J, Pornel B, Marton I, et al. Efficacy and acceptability of intranasal 17b-oestradiol for menopausal symptoms: randomised dose –response study. Lancet 1999;353:1574 –8. Mattsson LA, Christiansen C, Colau J-C, et al. Clinical equivalence of intranasal and oral 17b-estradiol for postmenopausal symptoms. Am J Obstet Gynecol 2000;182:545 – 52. Wiklund I, Karlberg J, Mattsson LA. Qualtity of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebo-controlled study. Am J Obstet Gynecol 1993;168:824 –30. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. Br Med J 1996;313:36 –9. Gompel A, Bergeron C, Jondet M, et al. Endometrial safety and tolerability of Aerodiol® intranasal estradiol for 1 year. Maturitas 2000;36:209 –15. Cano A. Compliance to hormone replacement therapy in menopausal women controlled in a third level academic centre. Maturitas 1994;20:91 –9. Faulkner DL, Young C, Hutchins D, McCollam JS. Patient noncompliance with hormone replacement therapy: a nationwide estimate using a large prescription claims database. Menopause 1998;5:226 –9. Bjorn I, Backsrom T. Drug related negative side-effects is a common reason for poor compliance in hormone replacement therapy. Maturitas 1999;32:77 –86.
[23] Ettinger B, Pressman A. Continuation of postmenopausal hormone replacement therapy in a large health maintenance organization: transdermal matrix patch versus oral estrogen therapy. Am J Manage Care 1999;5:779 – 85. [24] Christensen M, Hagen C, Christiansen C, Transbol IB. Dose– response evaluation of cyclic estrogen/gestagen in postmenopausal women: placebo-controlled trial of its gynecologic and metabolic actions. Am J Obstet Gynecol 1982;144:873 – 9. [25] Steingold KA, Laufer L, Chetkowski J, et al. Treatment of hot flashes with transdermal estradiol administration. J Clin Endocrinol Metab 1985;61:627 – 32. [26] Studd JWW, McCarthy K, Zemblera D, et al. Efficacy and tolerance of Menorest®, compared to Premarin® in the treatment of postmenopausal women. A randomised, multicentre, double-blind, double-dummy study. Maturitas 1995;22:105 – 14. [27] Bacchi-Modena A, Bolis P, Campagnoli C, et al. Efficacy and tolerability of Estraderm MX, a new estradiol matrix patch. Maturitas 1997;27:285 – 92. [28] Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol 1994;170:1213 – 23. [29] The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. J Am Med Assoc 1996;275:370 – 75. [30] Ferenczy A, Gelfand MM. Endometrial histology and bleeding patterns in postmenopausal women taking sequential, combined estradiol and dydrogesterone. Maturitas 1997;26:219 – 26. [31] Do¨ ren M, Schneider HPG. The impact of different HRT regimens on compliance. Int J Fertil Menopausal Stud 1996;41(Suppl. 1):362 – 71. [32] Pelissier C, de Kervasdoue A, Chuong VT, et al. Clinical evaluation, dose-finding and acceptability of Aerodiol®, the pulsed. Estrogen therapy for treatment of climacteric symptoms. Maturitas 2001;37:181 – 9.
Therapeutic value and long-term safety of pulsed estrogen therapy Martina Do¨ren a,*, Farook Al Azzawi b, Jacques Donnez c, Marius Jan Van der Mooren d, Jose´ Villero e, Anne Gompel f a
Free Uni6ersity of Berlin, Benjamin Franklin Uni6ersity Hospital, Clinical Research Center of Women’s Health, Berlin, Germany b Leicester Uni6ersity School of Medicine, Leicester, UK c Catholic Uni6ersity of Lou6ain, Brussels, Belgium d Department of Obstetrics and Gynaecology, Uni6ersity Hospital Vrije Uni6ersiteit, Amsterdam, The Netherlands e Hospital Reina Sofı´a, Co´rdoba, Spain f Department of Obstetrics and Gynaecology, Hoˆtel Dieu Hospital, Paris, France
Abstract Objecti6es: To demonstrate equivalent efficacy for menopausal symptoms between Aerodiol® nasal spray and reference oral estradiol therapy, and to investigate the endometrial safety and tolerability of Aerodiol in the long term. Methods: The efficacy of Aerodiol 300 mg, once daily, was compared with oral estradiol 2 mg/day in a randomized, double-blind trial. A statistical test of noninferiority was performed on the mean absolute Kupperman index (KI) obtained after 14 and 23 weeks of the two treatments. Long-term safety was assessed in a 1-year open-label study. The initial Aerodiol dose was 300 mg/day, and was adjusted if required. Endometrial biopsies were obtained at inclusion and at the end of the trial and examined independently by two pathologists. Results: In the equivalence trial, the KI improved similarly in the Aerodiol group (n= 317) and the oral estradiol group (n= 342). Aerodiol was shown statistically to be at least as effective as oral therapy (PB 0.001), but the incidences of mastalgia and withdrawal bleeding were significantly lower in the Aerodiol group (P B0.01 and P B 0.001, respectively). In the long-term safety trial (n= 408), the rate of Aerodiol treatment continuation at 12 months was 85%, and there was no incidence of endometrial hyperplasia or cancer. Aerodiol dose adaptation was performed by 29% of women. Conclusions: Aerodiol was shown to have equivalent efficacy to reference oral estradiol therapy, but with better gynaecological acceptability. The endometrial safety of Aerodiol was confirmed in the long term, and the ability to adjust the dosage easily was of benefit to a substantial proportion of women. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pulsed estrogen therapy; Estradiol nasal spray; Menopausal symptoms; Endometrial safety; Withdrawal bleeding
1. Introduction * Corresponding author. Tel.: + 49-30-84415811; fax: + 4930-84415819. E-mail address: [email protected] (M. Do¨ren).
Estrogen replacement therapy has been shown to be effective in reducing the vasomotor and urogenital symptoms of the menopause [1–3].
0378-5122/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0378-5122(01)00201-8
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Long-term estrogen supplementation is also effective in reducing the risk of low-trauma fractures due to postmenopausal bone loss [4,5] and the risk of cardiovascular disease [6]. The two most commonly used methods for the administration of estrogen supplementation are the oral and transdermal routes, but both have disadvantages. Oral estrogen is subject to substantial intestinal and hepatic first-pass metabolism [7,8], necessitating relatively high doses associated with high inter- and intraindividual variability and increased risk of gallbladder disease [9]. Transdermal administration, on the other hand, is associated with variable absorption rates between women [10], local skin irritation [11], and the loss of patches in 4– 8% of cases due to poor adhesion [12]. Aerodiol® is an aqueous solution of the natural 17b-estradiol delivered by a metered pump for intranasal administration, which represents a new approach to the treatment of menopausal symptoms. Aerodiol introduces the new concept of pulsed estrogen therapy. After nasal administration, plasma estradiol levels rise rapidly and fall to 10% of their peak level within approximately 2 h [13], unlike both oral and transdermal administration which produce prolonged or plateau estrogen elevations [14]. The efficacy of pulsed estrogen therapy in reducing postmenopausal symptoms has been demonstrated in a randomized, placebo-controlled trial [15], and 300 mg/day was identified as an appropriate initial dose. That trial also established the safety and tolerability of Aerodiol over a 12-week study period. However, the full benefits of estrogen supplementation require long-term therapy, so studies over a longer period of time are required. This paper describes studies performed with three main aims. The first aim was to demonstrate the equivalent efficacy of Aerodiol 300 mg/ day relative to a standard oral estradiol therapy of 2 mg/day. The second was to investigate the endometrial safety and tolerability of Aerodiol over a 1-year period. The third aim was to assess the therapeutic value of the potential benefits of Aerodiol, in terms of its general safety and the ease with which the dose can be adapted to suit individual needs.
2. Clinical efficacy of Aerodiol
2.1. Study design The equivalence of efficacy of Aerodiol 300 mg once daily to a standard dose of 2 mg/day of oral micronized estradiol was assessed in a randomized, double-blind, two-arm, parallel-group trial conducted in nine European countries [16]. Postmenopausal Caucasian women with moderate-tosevere menopausal symptoms, defined as a Kupperman index (KI) ] 15, were recruited to the trial. Women received either intranasal Aerodiol 300 mg (one spray in each nostril) plus an oral placebo capsule, or an oral estradiol 2 mg capsule plus placebo intranasal spray, every morning for 24 weeks. All women also received dydrogesterone 10 mg per day for 14 days per 28-day cycle. After 14 weeks’ therapy, the number of nasal sprays could be adjusted if there was evidence of over- or underdosage. The primary efficacy end point was the KI score after 14 weeks; the KI was also assessed at 23 weeks. The KI is a weighted evaluation of the incidence and severity of 11 of the most frequent menopausal symptoms, and has been extensively validated [1,17]. Of the symptoms included, hot flushes, night sweats, sleep disorders, and nervousness are weighted more heavily than depression, dizziness, tiredness, arthralgia, headache, palpitations, and vaginal dryness in the calculation of the index. In comparing KI scores between the two treatments, an equivalence limit of 9 4 points was set. This limit was determined before the start of the study by a scientific committee that included both statisticians and gynecologists specialized in hormone replacement therapy (HRT), and represents less than half the expected difference from placebo [18]. A one-tailed Student’s t-test was performed as a statistical test of noninferiority on the absolute mean KI scores; a significant result indicates that Aerodiol is at least as effective as the reference drug. The secondary efficacy end point was the number of hot flushes per day, which was assessed at weeks 14 and 23. Vaginal smears were taken at selection and at week 14, and endometrial samples were obtained at selection and at week 23. Bleeding patterns and
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the occurrence of genitourinary symptoms were recorded. Nasal tolerability was assessed in all women at week 14 and 23, and a subset of 199 women were examined by an ear, nose, and throat specialist before therapy and at week 23.
2.2. Results A total of 659 women were included and randomized. There were no differences in baseline characteristics between the groups (Table 1) and 559 women (85%) completed the trial. The majority of discontinuations were due to adverse events (28 in the intranasal group and 36 in the oral group). Compliance was extremely high (99% for the intranasal and 98% for the oral group at week 14). Adaptation of the number of sprays taken per day was required for 20% of women in the oral group and 22% in the intranasal group at week 14. After 14 weeks, the KI had decreased by a similar amount in both groups (Fig. 1). The difference between the mean KIs was 1.1, with a 90% confidence interval of 0.0– 2.2. The upper confidence limit was less than the predefined equivalence limit of + 4 points, indicating that Aerodiol 300 mg/day was at least as effective as oral estradiol 2 mg/day (P B0.001). Similar results were obtained after 23 weeks. Moreover, Aerodiol was also shown to be at least as effective as oral Table 1 Baseline demographic and clinical parameters of women in the clinical efficacy triala
Number of women Age (years) BMI (kg/m2) Age at menopause (years) Time since menopause (months) Previous hormone replacement therapy number (%) Daily incidence of hot flushesb a b
Aerodiol
Oral estradiol
317 51.0 9 4.2 25.19 3.9 48.29 4.2 39.19 33.8
342 51.2 9 4.2 25.3 94.2 48.8 9 4.1 35.4 933.7
134 (42)
145 (42)
6.19 3.7
6.4 94.4
Data are presented as mean 9S.D. unless indicated. During the preceding week.
Fig. 1. Mean KI ( 9S.D.) at baseline, week 14, and week 23 in women receiving Aerodiol 300 mg/day or oral micronized estradiol 2 mg/day.
therapy in two subgroups of women, those who had experienced more than seven hot flushes per day at baseline (P=0.01), and those who were smokers (\10 cigarettes per day; PB 0.001). Women in both the intranasal and oral therapy groups showed substantial and similar decreases in the incidence of hot flushes (Fig. 2). In both groups, the median incidence of hot flushes at week 14 and week 23 was zero. There were no significant differences between the intranasal and oral therapy groups in the frequency of genitourinary symptoms. The proportion of women with atrophic vaginal mucosa decreased from 28 and 29% at baseline to 1% in both treatment groups after 14 weeks. Improvement in the karyopyknotic index occurred in 90% of the Aerodiol group and 92% of the oral estradiol group.
2.3. Safety, tolerability, and acceptability The incidence of mastalgia was significantly lower in the Aerodiol group at both week 14 and 23. Moderate-to-severe mastalgia was reported in
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10% of women in the Aerodiol group and 16.5% in the oral estradiol group (P B 0.05). Five women prematurely stopped treatment due to mastalgia in the oral group, compared with none in the Aerodiol group (P B0.05). Significantly more women receiving oral therapy (69%) experienced withdrawal bleeding in all cycles than those receiving intranasal Aerodiol (49%), and the bleeding was of longer duration. No women in either group showed endometrial hyperplasia at baseline or after 23 weeks of study therapy. The rate of ‘atrophic’ endometrium was higher in the Aerodiol group (25%) than in the oral group (14%; Fig. 3). Thus pulsed estrogen therapy produced less stimulation of reproductive organs, such as the breast and endometrium, than oral therapy. Both therapies were well tolerated. There were only two serious adverse events related to the study therapy (one case of hematometra in each group). The incidence of adverse events was very similar in both groups; those related to treatment were of mild or moderate intensity in 95% of cases for the intranasal group and 90% for the oral
Fig. 2. Mean incidence of hot flushes ( 9 S.D.) at baseline, week 14, and week 23 in women receiving Aerodiol 300 mg/day or oral micronized estradiol 2 mg/day.
group. Nasal symptoms, including sneezing, itching, and rhinorrhea, were more frequent in the intranasal group, but only 1% of women in each group discontinued therapy prematurely as a result of local events. The acceptability of the nasal spray was recorded as good or excellent by 93 and 92% of women in the intranasal and oral therapy groups, respectively. Endometrial safety is an important issue with all forms of HRT, and is often a major concern for both the woman and the doctor. Although the results of this study indicated that Aerodiol induced less endometrial proliferation than oral estradiol of equivalent efficacy, it was important to investigate the endometrial safety and general acceptability of Aerodiol thoroughly over a longer period.
3. Long-term endometrial safety and tolerability
3.1. Study design The long-term endometrial safety and tolerability of Aerodiol was assessed over a 1-year period in an open-label, community-based, multicenter trial [19]. Postmenopausal, nonhysterectomized women who had completed a previous controlled study of Aerodiol and who wished to continue intranasal estradiol therapy for at least 1 year were recruited in six European countries. There was no mandatory washout period before entry and women could have received previously either different doses of nasal estradiol (from 100 to 900 mg/day) or placebo or micronized estradiol (1 or 2 mg) [15,16]. Initially, the women received Aerodiol 300 mg/ day as one spray of 150 mg in each nostril, either continuously or for 21–25 days/month. Dose adjustments were allowed at 3-monthly intervals if there were symptoms of under- or overdosage. Progestogen therapy was given for at least 12–14 days of each treatment cycle, as either a continuous or sequential regimen. A choice of five different progestogen therapies was available. Endometrial biopsies were obtained at study inclusion and after 12 months’ therapy. The histological material was assessed independently by
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Fig. 3. Classification of endometrial biopsies taken at week 23 in women receiving Aerodiol 300 mg/day (n =118) or oral micronized estradiol 2 mg/day (n = 114). No tissue indicates that the sample obtained was insufficient for histological analysis.
two pathologists who were blind to the therapy regimen. A consensus position was reached in all cases of disagreement. Cyclical and unexpected bleeding was assessed at quarterly interviews, at which any adverse events were also recorded.
3.2. Results A total of 408 women were recruited and 349 completed the study. Their mean age was 52.5 ( 9 3.9) years with body mass index (BMI) at 23.9 ( 9 3.4) and they had been menopaused for 3.2 ( 92.2) years. During the 1-year study period, 29% of women had their dose of Aerodiol increased or decreased at least once, by changing the number of sprays taken per day. The distributions of Aerodiol daily dosages during the first and last 3-month periods of the study are shown in Fig. 4. These distributions confirm that 300 mg/day is an appropriate dose both for initial and
long-term intranasal estradiol therapy. However, the ability to adjust the dose simply was a useful property for a substantial minority of women. Endometrial biopsies were available from 367 women at inclusion (M0) and 311 women after 12 months’ therapy (M12). Importantly, at M12 there was no incidence of cancer or endometrial hyperplasia (95% CI= 0–1.12), and the endometrium was mainly atrophic (34%) or secretory (39%). Only 2.8% of samples taken during the progestational phase were classified as proliferative. Biopsies were not taken at M12 for 38 women, because of either a narrow cervix or the woman’s refusal. For these women, vaginal ultrasound examination was used to rule out a significant endometrial abnormality. At quarterly interviews, cyclical bleeding was reported in 79–81% of sequential treatment cycles. Cyclical bleeding was of mild-to-average intensity in 92% of cycles at M3 and 98% of cycles at M12. Unexpected bleeding occurred in 15% of
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cycles with continuous therapy and in 4% of cycles with sequential cyclical therapy. Some 80% of unexpected bleeds were only spotting, and unexpected bleeding did not lead to premature treatment discontinuation in any women. One woman withdrew as a result of menorrhagia.
3.3. Tolerability and acceptability Aerodiol therapy was well tolerated, the rate of continuation of treatment at 12 months was 85%. This rate compares very favorably with that described in recent published studies of HRT administered by other routes [20– 23]. The most frequent adverse events were nasal symptoms, of which most were mild in intensity. Nasal events led to premature discontinuation of treatment in 14 (3.4%) women (nine for sneezing, three for nose itching, two for nose bleeding). All nasal events resolved spontaneously after discontinuation of treatment. Severe mastalgia was reported by 1.5% of women, and in one case led to premature withdrawal from treatment.
4. Comments The double-blind, double-dummy randomized trial described in this paper has established equivalent efficacy in the relief of menopausal symptoms between Aerodiol 300 mg/day and a widely used reference oral estrogen supplementation therapy, oral micronized estradiol 2 mg/day. This result was obtained for the study population as a whole, and for subpopulations of smokers and those with more severe menopausal symptoms at baseline. An important further result is that Aerodiol therapy demonstrated a lower stimulation of reproductive tissues (endometrium, breast) compared with the equivalent oral therapy. In addition, the long-term endometrial safety and tolerability of Aerodiol therapy were confirmed over a longer, 1-year study period. It had been suggested previously that Aerodiol 300 mg/day had a similar effect on the KI and the incidence of hot flushes as oral estradiol valerate 2 mg/day [15]. In the present study, the therapeutic equivalence of these two treatments with regard to
Fig. 4. Distribution of Aerodiol daily doses during the first (M0 – M3) and last (M9 – M12) 3-month period of the 1-year study.
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menopausal symptoms has been demonstrated formally, using a statistical test of noninferiority [18]. The improvements in the KI and the reductions in the incidence of hot flushes observed in the present study are similar to those reported previously for studies of oral and transdermal estrogen supplementation [24,25,27]. A previous placebo-controlled, dose-ranging study [15] identified 300 mg/day as an appropriate dose for initiating therapy with Aerodiol. The present studies have confirmed this and indicated that 300 mg/day is a satisfactory dose in the longer-term for the majority of women. However, the ability to adjust the dose of Aerodiol simply, without changing the dispenser, by increasing or decreasing the number of sprays taken per day was an important facility for a substantial minority of women. Pulsed estrogen therapy resulted in lower incidences of mastalgia and withdrawal bleeding than oral therapy over the 23-week study period, and this good gynecological acceptability was confirmed over 1 year. Intranasal therapy also showed a lower tendency to stimulate endometrial proliferation than the oral route, with a high incidence of atrophic endometrium maintained during the long-term study. Endometrial hyperplasia has an estimated incidence of 1– 2% after 1 year of combined HRT [28 –30]. No cases of endometrial hyperplasia or cancer were observed in either of the studies reported here involving more than 400 women. The reduced level of stimulation of the reproductive organs produced by Aerodiol compared with oral estradiol therapy of equivalent efficacy on climacteric symptoms may be related to the pulsed kinetic profile of estradiol exposure that occurs with the intranasal route [13]. The high level of gynecological acceptability of Aerodiol should encourage good compliance with therapy [31]. The intranasal route of administration was well tolerated. No new or additional nasal symptoms became apparent in these longer-term trials compared with previous studies of shorter duration [15–32]. The withdrawal rate due to local events compares favorably with that reported in a study of estrogen therapy by the transdermal patch [11]. The rate of treatment continuation that we ob-
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served after 1 year of therapy is high compared with some other published studies of HRT [20– 23]. Rates of continuation of HRT in the general population have recently been reported to be as low as approximately 33% [23] and less than 50% [21]. The present studies confirm that pulsed estrogen therapy provided by Aerodiol, in combination with continuous or sequential progestogen therapy, represents an effective, safe, well-tolerated, and highly acceptable form of HRT.
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