Continuous Versus Cyclical Transdermal Estrogen Replacement Therapy in Postmenopausal Women: Inﬂuence on Climacteric Symptoms, Body Weight and Bleeding Pattern

Maturitas 28 (1997) 117–125

Continuous versus cyclical transdermal estrogen replacement therapy in postmenopausal women: inﬂuence on climacteric symptoms, body weight and bleeding pattern

H. Lu¨bbert a,b,*, C. Nauert b

a Department of Gynecological Endocrinology, Benjamin Franklin Uni6ersity Hospital, D-12200 Berlin and Clinical Research Department, Rhoˆne-Poulenc Rorer, D-50829 Cologne, Germany b Abteilung fu¨r gyna¨kologische Endokrinologie, Benjamin Franklin Klinikum, Hindenburgdamm 30, D-12200 Berlin, Germany

Received 2 April 1997; received in revised form 11 August 1997; accepted 13 August 1997

Abstract

Objectives: To compare continuous and cyclical transdermal estrogen replacement therapy (ERT) with or without an oral progestogen regarding climacteric symptoms, body weight and bleeding pattern. Methods: A total of 2459 postmenopausal women were treated for three cycles of 28 days in an open, randomized, parallel group multicenter study. Patients received an estrogen matrix patch (50 vg17/i-estradiol/day) twice weekly, either continuously (eight patches/cycle) or cyclically (six patches/cycle, i.e. 3 weeks on, 1 week off). A total of 1232 patients were treated continuously and 1227 cyclically. In the study group 1150 patients had an intact uterus (543 in the continuous and 607 in the cyclical treatment arm) and received, in addition to the estrogen patch, an oral progestogen in a transformation dose for 12 days of each cycle. Hysterectomized patients totaling 1309 (689 in the continuous versus 620 in the cyclical group) did not receive progestogen. Of the 2459 patients, 771 (31.4%) participated in a follow-up study with two further treatment cycles, which was offered to the patients at the end of the main study. The main outcome measures were climacteric symptoms, measured at the end of cycles 1–3 by a Visual Analogue Scale at baseline, and body weight measured at baseline at the end of cycles 3 and 5. In addition, the bleeding time per cycle (days) was evaluated in all patients with an intact uterus. Results: Continuous and cyclical transdermal ERT reduced, over three treatment cycles, the average climacteric symptom score by 1.77 and 1.70, respectively. The percentage remission and improvement rates for the ten climacteric symptoms ranged between 69.3 and 88.0% and did not differ between the two groups. In patients with a higher symptom score at baseline, the continuous treatment was slightly more effective. However, this effect was statistically not signiﬁcant. After three treatment cycles body weight increased in both treatment groups by between 500 and 700 g. Further treatment during the follow-up study induced an additional average weight gain of 200–400 g. These results were not inﬂuenced by the addition of an oral

* Corresponding author. Tel.: +49 30 84452463; fax: +49 30 84454205.

0378-5122/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-5122(97)00067-4 118 H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125 progestogen. In patients with an intact uterus, the average bleeding time at the end of the first cycle (5.4 days in the continuous versus 5.3 days in the cyclical group) increased slightly during cycle 2 and returned to baseline values at the end of cycle 3. Conclusions: Continuous and cyclical transdermal ERT were equally effective in reducing climacteric symptoms. The short term use of five cycles transdermal ERT induced a slight increase in body weight which was independent of the treatment regimen. These results were not influenced by the type and mode of administration of a progestogen. Both ERT regimens were very well tolerated and are suitable alternatives for estrogen replacement therapy of postmenopausal women. © 1997 Elsevier Science Ireland Ltd.

Keywords: Climacteric symptoms; Menopause rating scale; Estrogen replacement therapy; Transdermal application; 17ß-estradiol; Body weight; Systemic tolerance; Local tolerance; Continuous therapy; Cyclical therapy; Bleeding pattern

1. Introduction study. In addition, the safety of both treatments and their influence on body weight were investi- Transdermal delivery systems for 17ß-estradiol gated over a treatment period of 5 months. Any effects of a progestogen treatment on the relief of (E2), such as patches, reduce the frequency of climacteric symptoms and or weight gain were to drug administration and provide E2 plasma con- / centrations which, in contrast to the oral route, be evaluated. Hysterectomized women, who did remain relatively constant over a period of 3–4 not receive progestogen, were compared, there- days [1,2]. fore, to non-hysterectomized women, who re- The first commercially available transdermal ceived a progestogen in a transformation dose for system was a reservoir patch, which was launched 12 days every 4 weeks. nearly 10 years ago [3]. Subsequently, the develop- ment of matrix patches led to improved local tolerance, which made these delivery systems 2. Subjects and methods more acceptable to the patient [4,5]. In addition, the pharmacokinetic properties of matrix patches 2.1. Patients are superior to those of the reservoir patch [6–8]. Despite these improvements and the broad ap- A total of 2459 postmenopausal women, older plicability of the therapeutic preparations, compli- than 40 years, who required estrogen replacement ance with ERT in postmenopausal women is still therapy (ERT), were included in this multicenter rather low [9,10]. Bleeding problems and weight study. Further inclusion criteria were: surgical or changes are the main reasons for discontinuation. natural menopause, the last natural bleeding hav- Reduction of these negative side-effects can be ing occurred at least 2 years before the start of the expected to improve compliance. In addition, study and/or with a serum FSH-level of more treatment regimens should be as uncomplicated as than 30 IU/landa17ß-estradiol level of less than possible. The continuous twice weekly application 30 pg/ml; gynecological investigation before the of an estrogen patch, for example, is easier for a start of the study, including mammography and patient to handle than the cyclical 3 weeks on, 1 PAP smear, without any contraindication for week off regimen. However, it is unclear whether ERT. A progestogen at a transformation dose these two treatment regimens are equally effective was prescribed for all patients with an intact in relieving climacteric symptoms. uterus for 12 days/cycle. The type of progestogen The aim of our study, therefore, was to com- was not specified by the protocol. However, the pare the relief of climacteric symptoms achieved use of medroxyprogesterone acetate (MPA), at a under either continuous or cyclical transdermal dose of 5 mg/day, was recommended. Exclusion ERT using a matrix patch, over a treatment pe- criteria were: undiagnosed vaginal bleedings, riod of 3 months, in a multicenter, parallel group known or suspected malignant diseases or other H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125 119 severe diseases; acute thromboembolism, relevant 2.3. Study design dermatologic diseases (including allergic reactions) and known allergies to patches or other The study was designed as an open, controlled, topical drugs. In addition, the use of any other parallel group multicenter study. Target patients sex hormones within 14 days of the start and were recruited by 469 gynecologists in Germany. during the study was not permitted. During the course of the study, two visits were All patients were informed of the study design to be made, at baseline and at the end of the last and the study procedures and gave their written treatment cycle. During the baseline visit, all in- informed consent to inclusion. The study proto- clusion and exclusion criteria were checked and col was approved by the Ethical Committee of the patients were randomized to the continuous the Benjamin Franklin University Hospital, and cyclical treatment groups following their in- Berlin and by 16 regional Ethical Committees in formed consent. All anamnestic data and con- Germany. comitant drug therapy were recorded and Of the 2459 patients, 771 (31.4%) participated efficacy parameters were evaluated. Compliance in a follow-up study, which was offered to the was controlled by counting the unused test medi- patients at the end of the main study. The inclu- cation at the end of the treatment. sion and exclusion criteria were not changed for this study extension and all participants had to Patients who were willing to participate in the give again their written informed consent. extension study received the new study medication according to the original randomization code at their second visit (i.e. the visit after three cycles of therapy). All inclusion and exclusion 2.2. Treatment criteria were checked again and the patients were asked to come back for a final visit after two The treatment period for both groups extended further treatment cycles. over three cycles of 28 days. Patients received an v 6 estrogen matrix patch (Menorest, 50 gE2/day) 2.4. Efficacy ariables twice weekly, either continuously (8 patches/cycle) or cyclically (6 patches/cycle, i.e. 3 weeks on, The main efficacy variable was the sum of 1 week off). Each package of testmedication con- climacteric symptoms and its reduction during tained two (cyclical treatment) or three (continu- the course of the study. The symptoms were ous treatment) reserve patches and instructions evaluated using the Menopause Rating Scale on the use of the patch. The patches were to be (MRS), which was developed recently [11]. This applied to a dry and hairless skin area, alter- scale allows a rating of ten different climacteric nately using the left and right side of the waist symptoms from 0.0 (no symptoms) to 10.0 or abdomen for each application. Non-hysterec- (severe symptoms) and provides an individual tomized women received a progestogen at a symptom profile for each patient. The scale was transformation dose for the last 12 days of each to be filled out by the patients during the two cycle. The type of the progestogen was not di- study visits (i.e. at baseline and at the end of rected by the protocol. However, the use of cycle 3) and at the end of cycles 1 and 2. Sec- medroxyprogesterone in a dose of 5 mg/day was ondary efficacy variables were the change in recommended. In addition the type and dose of body weight (determined at baseline and after the progestogens used were recorded. three and five treatment cycles) and the duration In a subgroup of patients the treatment period was prolonged for two further cycles of 28 days. of vaginal bleeding during cycles 1–3. All ad- During this follow-up study all participants re- verse events were recorded by the physicians and ceived the same treatment regimen as originally their possible causal connection with the randomized. testmedication was assessed. 120 H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125

Table 1 Use of different oral progestogens (type in % and dosage in mg) in non-hysterectomized women (n=1150)

Compound Total population (n= Continuous group (n= Cyclical group (n= Average daily 1150)543) 607) dosage

Norethisterone acetate 47.645.2 49.8 5.1 Medroxyprogesterone acetate 37.4 39.7 35.5 3.0 Medrogestone 10.5 10.4 10.6 5.0 Chlormadinone acetate and4.5 4.7 4.1 2.3a others

Type in % and dosage in mg.a Only chlormadinone acetate.

2.5. Data analysis excluded due to major protocol violations (i.e. age less than 40 years, therapy with sex hormones 2.5.1. Sample size determination during the wash-out phase or during the course of The main efﬁcacy variable (climacteric symp- the study). In the remaining continuous group toms) included 10 items and the total sumscore and in the cyclical group 151 and 138 patients was evaluated for each cycle. Additionally, a com- respectively terminated the study prematurely. parison was planned between the baseline score This was largely due to adverse events (30 versus and the individual last observation. On the basis 23) or to withdrawal of informed consent and/or of a coefﬁcient of variation of 500%, a sample size loss to follow-up (27 versus 26). Further reasons of 1167 patients/group was required (t-test for included missing data or violation of eligibility independent random samples, two-sided, experi- criteria. mentwise type-I-error rate of h=0.05, type-II-er- Of the 2459 patients, 772 (31.4%) participated ror rate of i=0.05, h-adjustment on the basis of in the follow-up study (401 in the continuous and 33 planned comparisons). 371 in the cyclical estrogen group).

2.5.2. Statistical methods 3.2. Demographic and baseline characteristics The confirmatory comparison of efficacy and safety data was planned on an intention to treat The two treatment groups were comparable basis. All treated patients were to be included, as with regard to their baseline characteristics. The randomized. All calculations, as well as table gen- mean age of the patients was 5497 years in both erations were performed using the statistical pack- treatment groups and their body weight was age SPSS 4.0 under the Interactive UNIX 69.8911.3 kg (continuous) and 69.2911.3 kg operating system at the computing facilities of the (cyclical), respectively. The mean pre-therapy Institut fu¨r Numerische Statistik, Cologne. MRS sumscore was 3.6291.62 for both treatment groups. In total, 1150 patients (47.7%) had an intact 3. Results uterus (543 in the continuous and 607 in the cyclical treatment arm) and received an oral 3.1. Study population progestogen at a transformation dose. The different progestogens and their mean dosages used for A total of 2459 postmenopausal women were this purpose are given in Table 1. The most included in this study (intention to treat popula- frequently prescribed compounds were norethis- tion). Of these patients, 1232 were treated in the teroneacetate (NETA, in 47% of cases) and continuous estrogen group and 1227 in the cycli- medroxyprogesteroneacetate (MPA, in 37% of cal estrogen group. Twenty five patients in the cases, see Table 1). A total of 1309 patients were continuous and 23 in the cyclical group were hysterectomized. These patients received only the H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125 121

Fig. 1. Relief of climacteric symptoms (MRS (Menopause Rating Scale ) sumscore, mean9S.D.) during three cycles of continuous v or cyclical transdermal estrogen replacement therapy with a matrix patch (50 gE2/day) in postmenopausal women (n=2459), for further explanation see Section 2.4. transdermal estrogen replacement therapy (689 ment in association with the magnitude of the continuous versus 620 cyclical treatment). symptom score at baseline. The higher the symptom score on inclusion, the higher was the differ- 3.3. Climacteric symptoms ence in the average symptom sumscore between the two groups at the end of cycle 1 (Fig. 2). This result During the course of the study, the MRS sum- was statistically not significant (paired t-test, P] score decreased on average by 1.77 points under 0.05). the continuous and by 1.70 points under the cyclical treatment regimen (Fig. 1). This difference 3.4. Body weight was not statistically significant. The remission and improvement rates for all ten climacteric symp- Body weight increased slightly during the course toms ranged between 70 and 90%, with the highest of the main study. This increase ranged between relief rate for hot flushes (88.0 versus 87.7%, Table 500 and 700 g and was similar in the continuous 2). Again, this improvement was almost identical and cyclical treatment groups. Moreover, there for both treatment groups (Table 2) and did not was no significant difference in weight gain be- differ between patients either receiving only trans- tween patients who did or did not receive an dermal estrogen replacement therapy (i.e. the hys- additional progestogen (i.e. non-hysterectomized terectomized patients) or transdermal estrogen and hysterectomized women, Fig. 3). Further treat- replacement therapy plus an additional oral ment during the follow-up study induced an addi- progestogen (i.e. all women with an intact uterus, tional weight gain of 200–400 g, which was also Table 3). independent from the treatment regimen (Fig. 3). The greatest relief of climacteric symptoms was achieved during the first treatment cycle (Fig. 1). 3.5. Vaginal bleeding During this period, a tendency towards greater symptom relief could be seen on continuous treat- The mean bleeding time of 5.3 to 5.4 days at 122 H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125

Table 2 3.6. Safety Percent remission and improvement rates for ten climacteric symptoms measured by the MRS in postmenopausal women (n=2459) after three cycles of continuous or cyclical transder- A sum of 438 adverse events were reported by v 272 patients (10.6%). A possible relationship to mal estrogen replacement therapy (50 gE2/day) the medication was given for 211 patients (8.6% Climacteric symptom Treatment group of the total population), equally divided between the cyclical and the continuous treatment groups. Continuous (n= Cyclical (n= 1232) 1227) The most frequently reported adverse events were topical allergic reactions (2.8%) with erythema Hot ﬂushes (%) 88.0 87.3 and pruritus in most of the cases and menorrha- Cardiac complaints 78.1 75.0 gia/dysmenorrhea (1.7%). Further frequently re- (%) ported events were breast pain (1.5%), headache Sleep disturbances 84.6 84.1 (%) (0.9%), weight increase (0.9%) and depression Depression (%) 80.2 80.8 (0.6%, Table 4). Serious adverse events were re- Nervousness (%) 80.1 80.0 ported in 14 patients (0.6%), with a possible rela- Decreased vitality (%) 74.9 74.6 tionship to the medication in one case (acute Sexual disorders (%) 69.3 72.1 depression requiring hospitalization). The inten- Urogenital complaints 75.8 72.6 (%) sity of the events was mild to moderate in the Vaginal dryness (%) 82.2 80.8 majority of cases. Muscle pain (%) 71.6 73.5

4. Discussion the end of the ﬁrst cycle increased slightly during cycle 2 and returned to baseline values at the end Continuous and cyclical transdermal estrogen of cycle 3. No major differences existed between treatment with a matrix patch at a dosage of 50 v the treatment groups. gE2/day induced comparable relief of climac-

Table 3 Percent remission and improvement rates for 10 climacteric symptoms measured by the MRS after three cycles of continuous or v cyclical transdermal estrogen replacement therapy (50 gE2/day) in postmenopausal women treated either with or without an oral progestogen (n=1150 versus n=1309)

Climacteric symptomTransdermal ERT plus progestogen (n= Transdermal ERT without progestogen (n=689+ 543+607=1150) 620=1309)

Continuous (n=543) Cyclical(n Continuous(n=689) Cyclical (n=620) =607)

Hot ﬂushes (%) 88.4 87.6 87.7 87.0 Cardiac complaints (%) 81.0 75.4 75.8 74.7 Sleep disturbances (%) 85.184.0 84.2 84.1 Depression (%)81.0 83.3 79.5 78.3 Nervousness (%)81.8 78.7 78.7 80.8 Decreased vitality (%) 77.7 76.3 72.5 73.0 Sexual disorders (%)72.5 73.4 66.8 70.8 Urogenital complaints (%) 76.6 71.7 75.2 73.4 Vaginal dryness (%)82.7 79.5 81.9 81.9 Muscle pain (%) 76.3 72.6 67.9 74.3 H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125 123

Fig. 2. Mean differences in the relief of climacteric symptoms measured by MRS (Menopause Rating Scale ) sumscore between v continuous or cyclical transdermal estrogen replacement therapy (50 gE2/day) after one cycle of therapy as a function of the MRS sumscore at baseline, for further explanation Section 2.4. teric symptoms. This was true for the mean MRS women. Over 80% of them will still be experienc- symptom score and for the ten different climac- ing flushes a year after onset and about 25% for teric symptoms measured separately. Similar re- the 5 years thereafter [14]. sults have been reported with oral HRT [12,13]. The additional administration of a progestogen Nevertheless, the average symptom score in the did not influence the symptom relief of any of the continuous treatment group was reduced slightly ten climacteric symptoms measured. This observa- more rapidly. In this group, a tendency for a tion supports previous results with different oral higher degree of symptom relief could be shown combination regimens of estrogen and progesto- in patients with a more severe baseline symptom gen, showing no major differences between the score. This effect was statistically not significant effects of various treatment combinations on cli- and could only be demonstrated during the first macteric symptoms [15,16]. cycle of therapy. Nevertheless, it should be further Different types of progestogen were used in the evaluated in controlled studies especially with subgroup of non-hysterectomized patients. This women showing stronger climacteric symptoms was allowed according to the protocol provided (e.g. younger women after ovariectomy or women the type and dose of the progestogen was stable in the first postmenopausal years). It could also be over the study period and consistent with the of importance when using lower dosages of trans- respective transformation dose [17]. As demon- v dermal ERT (e.g. 37.5 gE2/day), since differ- strated in Table 1 this prerequisite was fulfilled by ences in the efficacies of the two treatment the investigators. Under these prerequisites, the regimens might become more evident at low mean duration of vaginal bleedings per cycle was plasma estradiol levels. With both treatment regi- somewhat higher (0.1–0.3 days) in the continuous mens, the highest remission and improvement treatment group, but probably this is not clini- rates were observed for hot flushes. This symptom cally relevant. Additionally, the reported number affects approximately 70–80% of postmenopausal of patients with dysmenorrhea and/or menorrha- 124 H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125

Fig. 3. Mean body weight (kg) postmenopausal women before and after three cycles (n=2459) and five cycles (n=772) of continuous or cyclical transdermal estrogen replacement therapy (50 vg/day) and in subgroups of the same women treated either with or without an oral progestogen (n=1150 versus n=1309) gia was similar in both groups (20 versus 21 The average weight gain was 500–700 g and did patients). These results seem to be reasonable, not differ between the two transdermal ERT since most investigators probably did not change groups nor between the subgroups of opposed the previous progestogen prescriptions for their and unopposed ERT. The further ERT over two patients during this study. Due to this fact major cycles in the follow-up phase of the study slightly influences of the slightly different estrogen regi- increased this effect. However, the average weight mens on the bleeding pattern cannot be expected. gain was less than 1 kg in both treatment arms. Weight gain is one of the main reasons why The main reason for this effect was probably postmenopausal women discontinue ERT. As acute retention of extracellular fluid under estro- demonstrated in our investigation, a small in- gen influence. Other authors have shown that crease in body weight occurred in both treatment prolonged HRT does not induce a major weight groups over a period of three treatment cycles. increase in postmenopausal women. Even over a

Table 4 Most frequently reported adverse events (number of patients (percentage of patients)) in postmenopausal women (n=2459) during v three cycles of continuous or cyclical transdermal estrogen replacement therapy (50 gE2/day)

Total group (n=2459) Continuous group (n=1232) Cyclical group (n=1227)

Topical adverse event 69 (2.8%) 35 (2.8%) 34 (2.8%) Menorrhagia/dysmenorrhea 41 (1.7%) 20 (1.6%) 21 (1.7%) Breast pain 37 (1.5%) 19 (1.5%) 18 (1.5%) Headache 21 (0.9%) 9 (0.7%) 12 (1.0%) Weight gain21 (0.9%) 9 (0.7%) 12 (1.0%) Depression 15 (0.6%) 7 (0.6%) 8 (0.7%) H. Lu¨bbert, C. Nauert / Maturitas 28 (1997) 117–125 125 period of 15 years or more, the weight gain and ment therapies. Int J Fertil 1993;38:5–11. central obesity that is commonly observed in post- [6] Le Roux Y, Borg ML, Sibille M, et al. Bioavailability study of Menorest®, a new estrogen transdermal delivery system, menopausal women cannot be attributed to HRT compared with a transdermal reservoir system. Clin Drug [18–20]. However, the shift of gynoid to android fat Invest 1995;10:172–8. distribution is possibly reducd by HRT [20]. [7] Setnikar I, Rovati LC, Vens-Capell B, Hilgenstock C. Both treatment regimens were tolerated very well. Bioavailability of estradiol from two transdermal patches. 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