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The effects of continuous combined transdermal oestrogen-progestogen treatment on bleeding patterns and the endometrium in postmenopausal women
JOURNAL OF THE CLIMACTERIC 8 POSTMENOPAUSE
Maturitas 21 (1995) 211-219
The effects of continuous combined transdermal oestrogenprogestogen treatment on bleeding patterns and the endometrium in postmenopausal women H.P. Oosterbaan* a, A.H.J.A.M. van Buurenb, J.H.N. Schramc, P.J.H. van Kempend, J.M.H. Ubachse, H.A.I.M. van Lewden’, G.P.J. Beyerg aBosch Medieentrum,
Locatie
Groot Ziekengasthuis, Department of Obstetrics and Gynaecology, 5211 NL S-Hertogenbosch, The Netherlands bMedical Department, Ciba-Geigy Ltd, Arnhem, The Netherlands ‘Drechtsteden Hospital, Zwijndrecht, The Netherlands ‘Hospital Gelderse Vallei, Wageningen. The Netherlands eDe Wever Hospital, Heerlen. The Netherlands fHospital Rijnstate. Arnhem, The Netherlands BThe Red Cross Hospital, The Hague, The Netherlands
Nieuwstraat
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Received 28 April 1994; accepted 24 November 1994
Abstract
Fifty postmenopausal womenrequiring hormonereplacementtherapy for the treatmentof climactericsymptoms were recruited in six centers.All patients receiveda new combinednorethisteroneacetate(NETA)/oestradiol (EJ‘ITS, (EstragestTTS, Ciba-GeigyLtd), delivering0.25mg NETA and 50 gg E, per day, continuouslyfor 12calendar months.Bleedingoccurredin 38 (76%)of the 50 patientsat any time during the 1 year treatment.The percentageof patientswithout bleedingincreasedgradually eachmonth, from 24% in the secondmonth to a relatively stablelevel of - 80%in month 7 and thereafter.Twenty-sevenpatients(54%)did not completethe wholetrial period; 15of which discontinuedthe treatmentwithin the tirst few monthsdueto irregularbleeding.In patientswho remainedin the trial, a clear decrease in the frequency and intensity of the bleedingwasobservedwith time. Bleedingwasmostly light or consistedof spotting only. None of the post-trial biopsiesshowedproliferation or hyperplasiaof the endometrium. The treatmentresultedin a substantialdecreaseof climactericsymptoms(Kuppermanindex) within 4 monthsand was well tolerated. It was concluded that the continuous NETA/E,-‘ITS the treatmentof climactericsymptomsin selectedpatients. Keywords:
l
Transdermal;
Postmenopausal
women; Continuous
treatment
oestrogen-progestogen
Corresponding author
0378-5122/95/$09.50 SSDI
0378-5
0 1995 Elsevier Science Ireland Ltd. All rights reserved
122(94)00891-A
is an effective and safe alternative
treatment
for
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1. Introduction
2. Subjects and methods
An increasing number of women are currently using hormone replacement therapy (HRT) to alleviate climacteric symptoms [l] or in the prevention of postmenopausal osteoporosis [2]. In order to avoid the risk of endometrial cancer, the oestrogen treatment should be combined with progestogen administration [3]. Most regimens use sequential oestrogemprogestogen combinations, which result in a regular withdrawal bleeding in the majority of women. Bleeding is disliked by most patients and can lead to problems with compliance [4]. Oral continuous combined oestrogenlprogestogen treatments, in which the oestrogen and progestogen are given daily, have been tried in various dosages and these regimens produce amenorrhoea in several patients (up to 70%) within a few months [S-14]. Side effects that were encountered with this type of therapy have been irregular bleeding, especially during the first few months, and unwanted physical and psychological problems from the progestogen. Transdermal treatment with a norethisterone acetate (NETA)/estradiol (E,)-TTS (Estragest TTS, Ciba-Geigy Ltd) delivering 0.25 mg NETA and 50 pg E2 per day, in sequence with Estraderm TTS 50 has been established to be efficacious in the control of menopausal symptoms and of bleeding, and in the prevention of endometrial hyperplasia [15-181. The same combined NETA/E,-TTS was used in small single center studies using a continuous schedule [19-211. Although initial bleeding was relatively frequent, this improved rapidly during the first 6 months and further during the extension period. It appeared that patients who had not experienced any bleeding for a prolonged period prior to starting the therapy had a higher chance of remaining amenorrhoic, while no endometrial anomalies were detected. The present trial was designed to evaluate the effects of the continuous combined treatment of NETA/E?-TTS in a larger number of patients with regard to the occurrence and intensity of uterine bleeding as well as on endometrial histology after 12 months treatment.
The trial was designed as an open noncomparative, multicenter trial. After approval of the responsible ethical review boards, written informed consent was obtained from each eligible patient entering the study. 2.1. Patients Fifty healthy postmenopausal patients requiring oestrogen replacement therapy for treatment of climacteric symptoms were recruited in six centers. At enrolment, the patients either had the last menstrual bleeding more than 12 months ago, no previous hormone replacement therapy and a negative gestagen challenge test (10 days 10 mg medroxyprogesterone-acetate (MPA)), or previous oestrogen and sequential gestagen therapy with regular or no withdrawal bleeding episodes at the end of the gestagen treatment period. The last treatment dose should have been given more than 14 days prior to the start of trial treatment. If the gestagen challenge test resulted in bleeding, an endometrial biopsy had to be performed, which should have been normal. At the first visit the eligibility of a patient for the trial was assessed on the basis of the medicaYgynaecologica1 history and a full physical examination. A mammography, if not performed during the previous year, was carried out. Menopausal symptoms were evaluated by the Kupperman index [22], ranging from 0 to 51, and the trial procedure was explained. 2.2. Methods Two weeks after the initial visit, the Kupperman index was repeated and any bleeding events of the previous period were recorded. If the Kupperman index was 14 or more, the patients received diaries and trial medication for 3 months. Patients received calender packs, each containing 10 combined NETA/E,-TTS (Estragest TTS, Ciba-Geigy Ltd), delivering 0.25 mg NETA and 50 pg E2 per day, to be replaced every 3 or 4 days. Eight or nine patches were required per month. The remaining patches were kept as spares, and used when patches came off and could not be reapplied.
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Table 1 Patient characteristics recorded at first visit (n = 50)
Age
Mean Standard deviation Range
Height (cm)
Weight (kg)
Blood pressure (mmHg) Systolic
Diastolic
Months since LMP
Duration of menopausal symptoms (months)
50.9 4.9
166.5 6.5
64.3 8.1
130 13
79 9
47.8 32.0
45.6 30.0
34-59
152-180
50-83
90-170
50-95
S-144
9-144
LMP, last menstrual period.
In the 3rd or 4th treatment month, and again in the 6th or 7th month, the patient’s diaries were examined and any adverse experiences, changes in concomitant disease and medication were recorded while the Kuppennan index was repeated. Medication and diaries for the following period were supplied. At the last visit, after 12 months of treatment a full physical and gynaecological examination was performed. An endometrial biopsy (VABRA or comparable technique) was performed and all samples were evaluated by a pathology laboratory according to the following categories: inadequate for assessment, atrophic, proliferative (presence of one or more mitoses), hyperplasia (cystic or adenomatous, simple or atypical), secretory (secretory granulae) and non-secretory (no mitoses, no secretory granulae). The frequency, intensity and duration of vaginal bleeding during the 12 months was recorded in the patient’s diary. The number of bleeding episodes (i.e. a continuous sequence of bleeding days interrupted by no more than 1 bleeding free day), the total number of days of bleeding and the number of days of different intensity, per treatment month, were determined. The patient was asked to rate skin tolerability and adhesion and at each visit the skin application sites were examined by the physician. 2.3. Statistical methods The study population and the effects of therapy are presented by descriptive statistics. For the
Kupperman index, blood pressure and weight an end-point analysis (last available assessment compared to baseline) was performed. 3. Results
3.1. Patient characteristics The characteristics of the patients are shown in Table 1. With a mean age of 5 1 and a menopausal age of - 4 years these women had a relatively early menopause. At the start of the trial patients who would discontinue trial treatment prematurely were, on average, more than 6 kg heavier than patients who completed trial treatment (67.2 vs. 60.9 kg). The distribution of the patients over previous hormonal therapy and menopausal age is given in Table 2. Except for one patient (mastopathy) all mammography findings were normal. In total, 38 paTable 2 Distribution of patients over previous hormonal therapy and menopausal age Years since menopause l-38 Previous hormonal therapy 14 No Yes 10 Total 24 %cluding
>3-5
>5
4 8 12
7 7 14
Total
25 25 50
one patient who was 5 months postmenopausal.
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b
1
2
3
4 5 6 7 6 Month oftialtreatment
910
1112
1234567 Monthoftlfaitr6atm6nt
EpkocbscJ0E31~2iB2Y3~4~5
Epbod8snoel6sTiiJ2m2Y3~4~5 -
Numbrontopufbarismeannumberof@sodesperpaU6nt
Nmbarontopdbarlamaannumberd~perpelient
16
16 C
I4
14
12
12
8$1
f l'tl
0
0
%
42
r
0 1
2
3
4
5
6
7
6
Q 10
11 12
6llgMl%?aMcdllNn-m
42
i
0 1234567
MonthdW-
MmMhdbld~
6walnyzc76pd6nQ~
s
60verl&O6pdIhQ~
3ngMaasarMadllml-6tmnQ
Fig. 1. (a) Bleeding episodes per month for completed patients; (b) bleeding episodes per month for discontinued patients; (c) mean number of days with bleeding per month for completed patients; (d) mean number of days with bleeding per month for discontinued patients.
tients underwent an MPA challenge test. Four of them experienced a short bleeding of l-5 days duration which began 4-14 days after the start of MPA. In total, six endometrial biopsies were performed prior to treatment, which all proved to be atrophic. 3.2, Premature discontinuation Twenty-seven patients (54%) did not complete the whole study period; the treatment duration of
these patients ranged from 10 to 237 days. The main reason for discontinuing treatment was poor tolerability (n = 19), including unsatisfactory therapeutic effect (n = 4). Fifteen patients mentioned bleeding problems among the reasons for discontinuation of treatment. In six patients, local tolerability problems caused discontinuation of the trial medication. In one patient unsatisfactory therapeutic effect was mentioned as the only cause for discontinuation. One patient had to stop treat-
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.~ 4
A--
5
6
7
8
9
L
10
11
12
months
Fig. 2. The percentage of patients without bleeding per month ( -.-.-) related to patients in study; ( - + -) related to all patients started.
ment due to hypertension, which was already present before the start of the trial. 3.3, Occurrence of bleeding
Bleeding at any time occurred in 38 patients (76%), of which 16 patients (32%) completed the trial and 22 patients (44%) discontinued treatment prematurely. For twelve patients (24%) no bleeding was reported during the whole treatment period, of which 7 (14%) completed the trial. 3.4. Bleeding episodes,days and intensity
The mean number of bleeding episodes per treatment month decreased gradually from 0.9 (month 2) to 0.2 (month 12) for completing patients (Fig. la), and ranged from 0.9 (month 5) to
2.1 (month 4) for discontinuing patients without an improvement over time (Fig. lb). The number of patients who completed the trial with no bleeding episodes increased markedly from 9 (39%) in the first 2 months of treatment to about 18 (78%) after 6 months of treatment (Fig. la). The mean number of days with blood loss per treatment month gradually decreased and ranged from 3.9 (month 2) to 0.2 (month 12) for completing patients (Fig. lc). Also, for discontinuing patients an improvement was observed (Fig. Id) from 14.5 (month 2) to 9.1 (month 6). This was most probably due to discontinuation of heavy bleeders. Most of the bleeding in completing patients consisted of spotting (44%) or slight bleeding (40%), while strong bleeding occurred only once, for a period of 2 days in the third month of trial treatment. In addition, most of the bleeding consisted of spotting (47%) or slight bleeding (36%) for discontinuing patients. The percentage of patients without bleeding in any one month increased gradually, from 24% in the second month of treatment to a relatively stable level of about 800/o (fluctuating within a range of - 10%) in the 7th month and thereafter (Fig. 2). The increase reflects both the discontinuation of patients with frequent bleeding as well as the improvement in completing patients. The percentage of patients without bleeding in any one month related to the 50 patients who started the study only slightly increased from 28% in the first treatment month to 42% in the 7th treatment month, whereafter a stabilization to 36% was observed. It
Table 3 Patients categorized according to bleeding pattern No. of patients Trial completed PDa
Never bled or in one month only Bled every month or except in one month Mixed pattern
Reason for PD Bleeding as bleeding Month l-6
Month 7-12
13
8
5
0
I
0
22
2
20
15
22
6b
15
13
2
0
15
5
aPremature discontinuation; bmost of the patients discontinued during the first 6 months.
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Table 4 Endometrial biopsies, amount and histology at the end of treatment Biopsy material
Histology
Total None Small Moderate no. of obtained amount amount biopsies Non-bleeding patients Bleeding patients All
Abundant amount
Inadequate for assessment
Atrophic
Proliferative
Hyper- Secre- Nonplasia tory secretory
6
1
5
0
0
6
0
0
0
0
0
23 29
2 3
20 25
1 1
0 0
13 19
8 8
0 0
0 0
0 0
2 2
appeared that among patients with a menopausal age of 3-5 years, more amenorrhoea (up to 75%) was observed than among patients with menopausal age less than 3 years or more than 5 years. Among patients with previous hormonal therapy there was also more amenorrhoea (up to 48%) observed than among patients without such therapy. Table 3 categorizes the patients into a group that never bled or bled in 1 month only, patients who bled every month or except in 1 month and those with a mixed pattern of bleeding, respectively. Patients who had amenorrhoea from the beginning of the therapy usually remained amenorrhoic. Most of the patients who bled every month during the first months discontinued the treatment before month 6 and almost all mentioned bleeding as the main reason for stopping the trial. Patients who only bled during some of the first months mostly continued treatment and showed amenorrhoea or a clear decrease of bleeding after the first 6 months. 3.5. Endometrial biopsies The results of the 29 biopsies performed at the end of the trial treatment period are summarized in Table 4. Post-trial biopsies were performed in 21 out of the 23 completing patients and in 8 out of the 27 discontinuing patients. No biopsy material was obtained in three patients. In the remaining 26 patients, only a small or moderate amount of material was obtained; 16 of these biopsies were inadequate for assessment, 8 were atrophic and 2
non-secretory. In patients who experienced bleeding during the study the biopsies were either inadequate for assessment (n = 13), atrophic (n = 8) or non-secretory (n = 2). There was no sign of endometrial hyperplasia or proliferative endometrium. 3.6. Kupperman index The mean total score of the Kupperman in&x, as recorded at visit 2 was 25.2 (range 8-42) for all patients, 26.8 (range 15-42) for completing patients and 23.8 (range 8-34) for discontinuing patients. One patient had a Kupperman score of only 8 at visit 2 and should have been excluded. A large decrease of the Kupperman index was observed during the first 4 months of the trial period, followed by a relatively stable period during which the score levelled around values of 8. In the end-point analysis a significant decrease (P < 0.001) was observed when compared to baseline. At the end of treatment the mean index was 8.1 (range O-25) for all patients, 7.1 (range O-25) for completing patients and 8.9 (range O-24) for discontinuing patients. 3.7. Systemic and local tolerability Mean body weight and systolic and diastolic blood pressure did not change (P > 0.10). On physical examination, no abnormal lindings occurred during the study period. Painful or tender breasts were reported by 5 patients. The majority of the patients, both discontinuing
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and completing the study, regarded the skin tolerability and adhesion as good to very good. Skin tolerability was judged as poor by seven patients, of whom only one completed the trial. The majority (72) of the IO!9 observations on the skin sites of the last patch applied revealed no traces of irritation. Erythema was noticed thirty times, swelling was observed four times, scales twice and papules once. No serious adverse events occurred during the study. 3.8. Compliance
Based on the number of used patches returned and the quality of the diaries compliance was judged as good. 4. Discus5ion
In this study the efficacy and tolerability of continuous combined treatment with NETA/E,-TTS (Estragest TTS) was investigated in an open nonrandomized design in 50 patients. The main parameters were the frequency, intensity and duration of bleeding, as well as the endometrial histology. Bleeding occurred in 38 (76%) of 50 patients at any time during the 1 year treatment. Both the duration as well as the intensity of bleeding decreased in time. Bleeding was mostly light or consisted of only spotting. Amenorrhoea became more frequent with time; this was preferentially due to discontinuation by bleeding patients, although a decrease was also observed in the completing patients. It was shown that patients who had amenorrhoea from the beginning of the therapy usually remained amenorrhoic. In 15 of the patients bleeding problems were mentioned among the reasons for premature discontinuation. The percentage of patients without bleeding in any one month related to all 50 patients who started the study increased only from 28% in the first treatment month to 42% in the 7th treatment month, with a subsequent stabilization to 36%. Our results seem to be slightly better than the recent findings with two oral regimens of continuous combined therapy [13], where one third of the women had amenorrhoea by week 78 of therapy, while 62% of the women had withdrawn mainly
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due to chronic bleeding. In contrast to this study, no dose adjustments were allowed in our study protocol. Compared to another study [12] using two oral continuous regimens our results are quite comparable. In the early studies with continuous combined therapy, higher percentages of amenorrhoea are found [5-81, due to the fact that withdrawals were not considered. Furthermore, those early studies were performed by one investigator, whereas our study took place in six centers with a very large inter-center variation with regard to the number of drop outs (range 25- 100%). Our patients were also relatively young (mean age 51 years) and it is known that younger patients have a higher risk of irregular bleeding with this type of treatment [5,6]. Various patient characteristics such as age, menopausal age, previous sequential therapy and weight seem to influence the bleeding pattern. Patients with previous hormonal treatment bled less frequently and shorter than patients without prior treatment. However, in other studies [13,20] patients who had received sequential therapy prior to continuous combined therapy had more bleeding. More amenorrhoea was observed in patients (n = 12) between 3 and 5 years postmenopausal than in patients with a menopausal age of less than 3 years (n = 24) or more than 5 years (n = 14). It has been repeatedly found [5,6] that older patients and patients with a menopausal age of a few years respond better to this type of treatment than perimenopausal women. The results in the 14 patients with a menopausal age of more than 5 years could be explained by accidentally more bleeding from an atrophic endometrium. At the start of the trial patients who would discontinue prematurely were, on average, more than 6 kg heavier than patients who completed the trial treatment. The same was found by Sporrong et al. [1 1] and could be explained by additional bleeding in this group as a result of a higher conversion of androgens into oestrogens in the subcutaneous adipose tissue. Different suggestions have been made to predict patients that will be amenorrhoic with continuous combined therapy [6,8,11,13]. However, the results of the different studies do not agree and there
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is no consensus as yet as to which patients have a high chance of becoming amenorrhoic. It is interesting that in another study [24] with transderma1 continuous combined therapy using a lower dose of NETA/Ez 0.125 mgl25 pg per day, almost no bleeding was observed in older (1 58 years) women. A greater counteractive effect of oestrogen stimulation of the endometrium by adding progestogens continuously was suggested earlier [20]. There was no sign of endometrial hyperplasia in the biopsies at the end of the trial treatment. All biopsies were either inadequate for assessment or atrophic except for two biopsies in the bleeding patients that were non-secretory. These results show that, comparable to oral regimens [9,10,13], the oestrogenic effect on the endometrium is well antagonized by the progestagen with transdermal continuous combined therapy. In the light of the two cases of adenocarcinoma of the endometrium found in a long-term follow-up study [23] in patients using oral conjugated oestrogens combined with norethindrone, careful follow-up of these patients is still required. However, before combined treatment was started one of these patients was on an unopposed regimen, while the other used a sequential regimen over a longer period. The Kupperman index dropped from 25.2 to 8.1, so the control of menopausal symptoms was adequate. This was to be expected as the amount of estradiol delivered per day is the same as with Estraderm TTS 50. General tolerability of the treatment was good. Neither blood pressure nor weight were altered. Besides bleeding problems, painful or tender breasts and dermatological problems were the most frequently reported side effects. The good compliance can partially be accounted for by the good tolerability. In most patients the judgement of skin tolerability and adhesion as well as the overall assessment of tolerability was regarded as very good to good. Of the 23 patients who completed the trial, seventeen were willing to receive the same therapy for further alleviation of their menopausal symptoms.
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5. Conclusions In this study it was shown that treatment with continuous combined estradiol/norethisterone acetate TTS (NETA/E2-‘ITS) can be expected to be as safe as oral hormonal combined replacement regimens. This type of treatment is especially suited for patients accepting the risk of irregular bleeding during the initial treatment period. Efficacy in the control of climacteric symptoms was good and was maintained during the whole trial. Systemic and local tolerability also proved to be good. The results of post-trial endometrial biopsies suggest that the treatment does not stimulate proliferation of the endometrium after 1 year treatment. Nevertheless, careful monitoring of endometrial development by, for example, ultrasound and/or regular endometrial sampling for histology, still seem to be mandatory in long-term combined treatment. Furthermore, phase 3 trials to characterize the population that is most suitable for this type of treatment and to investigate possible metabolic effects are ongoing. Acknowledgements The authors wish to thank H. Hollema, M.D. Ph.D., gynecopathologist, University Hospital of Groningen for his evaluation of the biopsies. The work of J.P.J.M. Pfeil, MSc, head statistical department, L.A.B. Benelux, Arnhem, The Netherlands is also greatly appreciated. Finally we thank Dr. L. Schenkel, Ciba-Geigy, Switzerland for her critical evaluation of the manuscript. References [I] Campbell S, Whitehead M. Oestrogen therapy and the menopause syndrome. Clin Obstet Gynaecol 1977; 4: 31-47.
[2] Weis NS, Ure CC, Ballard JH. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of oestrogen. N Eng J Med 1980; 303: 1195-g. [3] Whitehead MI, Townsend PT, Pryse-Davies J, Path FRC, Ryder TA, King RJB. Effects of estrogens and
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progestins on the biochemistry and morphology of the menopausal endometrium. N Engl J Med 1981; 305: 1599-605. [4] Ryan PJ, Harrison R, Blake GM, Fogelman I. Compliance with hormone replacement therapy after screening for postmenopausal osteoporosis. Br J Obstet Gynaecol 1992; 99: 325-8. [5] Staland B. Continuous treatment with natural oestrogens and progestogens. A method to avoid endometrial stimulation. Maturitas 1981; 3: 145-56. [6] Mattsson LA, Cullberg G, Samsioe G. Evaluation of a continuous oestrogen-progestogen regimen for climacteric complaints. Maturitas 1982; 4: 95-102. [7] Magos AL, Brincat M, Studd JWW, Wardle P, Schlesinger P, O’Dowd T. Amenorrhea and endometrial atrophy with continuous oral estrogen and progestagen therapy in postmenopausal women. Obstet Gynecol 1985; 65: 496-9. [S] Staland B. Continuous treatment with a combination of estrogen and gestagen - a way of avoiding endometrial stimulation. Acta Obstet Gynecol Stand 1985; Suppl. 130: 29-35. 191 Bewtra C, Kable WT, Gallagher JC. Endometrial histology and bleeding patterns in menopausal women treated with estrogen and continuous or cyclic progestogen. J Reprod Med 1988; 33: 205-8. [IO] Hovik P, Sundsbeck HP, Gaasemyr M, Sandvik L. Comparison of continuous and sequential oestrogenprogestogen treatment in women with climacteric symptoms. Maturitas 1989; 11: 75-82. [ 1I] Sporrong T, Samsioe G, Larsen S, Mattsson LA. A novel statistical approach to analysis of bleeding patterns during continuous hormone replacement therapy. Maturitas 1989; 11: 209-15. [12] Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous and sequential oestrogen-progestogen treatment in women with climacteric symptoms. Maturitas 1989; II: 75-82. [ 131 Hillard TC, Siddle NC, Whitehead MI, Fraser DI, PryseDavies J. Continuous combined conjugated equine estrogen-progestogen therapy: Effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis. Am J Obstet Gynecol 1992; 167: 1-7. (141 Obel EB, Munk-Jensen N, Svenstrup B et al. A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment. Maturitas 1993; 16: 13-21.
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[15] Schenkel L. Development of a combined estradiolnorethisterone acetate ‘ITS. In: Transdermal Hormone Replacement therapy. Eds. Whitehead MI and Schenkel L. Camforth UK: Parthenon Publishing, 1988; 59-65. [16] Whitehead MI, Fraser D, Schenkel L, Crook D, Stevenson JC. Transdetmal administration of oestrogen/progestagen hormone replacement therapy. Lancet 1990; 335: 310-2. [17] Gangar K. Endometrial histology and bleeding patterns during administration of continuous oestradiol and sequential transdermal norethisterone acetate. In: Whitehead MI, Schenkel L, eds. Transdermal Hormone Replacement Therapy. Long-term Effects. Camforth: Parthenon Publishing, 1990; 67-70. [18] Lindgren R, Risberg B, Hammar M, Berg G, PryseDavies J. Endometrial effects of transdermal estradiohnorethisterone acetate. Maturitas 1992; 15: 71-8. [19] Uvebrant M. Continuous transdermal administration of combined oestrogen/progestogen for climacteric symptoms. Presented at the Sixth International Congress on the Menopause, Bangkok, Thailand, 1990. Abstracts. Camforth: Parthenon Publishing, 1990; Abstr. 247: 251. [20] Schenkel L, Hillard TC, Fraser D, Ellerington M, Whitehead MI. Transdermal continuous combined oestrogetigestagen therapy: development of amenorrhoea over 18 months. Int J Gynecol Obstet. Abstracts. XIII World Congress of Gynaecology and Obstetrics (FIGG), Singapore, 1991. Abstr. 1198. [21] Keller PJ, Hotz E, Imthurn B. A transdennal regimen for continuous combined hormone replacement therapy in the menopause. Maturitas 1992; 15: 195-8. [22] Kupperman HS, Blatt MHG, Wiesbader H, Filler W. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrhea] indices. Endocrinology 1953; 13: 688-703. [23] Leather AT, Sawas M, Studd JWW. Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women. Obstet Gynecol 1991; 78: 1008-10. [24] Hillard T, Ellerington M, Whitcroft S, Godvree V, PryseDavies J, Whitehead MI. The effect of low dose transderma1 continuous combined oestrogen and progestogen on breast tenderness, vaginal bleeding and endometrial stimulation. An ideal treatment for the “older” woman? Presented at the Sixth International Congress on the Menopause, Bangkok, Thailand, 1990. Abstracts. Camforth: Parthenon Publishing, 1990; 91, Abstr. 87.
Maturitas 21 (1995) 211-219
The effects of continuous combined transdermal oestrogenprogestogen treatment on bleeding patterns and the endometrium in postmenopausal women H.P. Oosterbaan* a, A.H.J.A.M. van Buurenb, J.H.N. Schramc, P.J.H. van Kempend, J.M.H. Ubachse, H.A.I.M. van Lewden’, G.P.J. Beyerg aBosch Medieentrum,
Locatie
Groot Ziekengasthuis, Department of Obstetrics and Gynaecology, 5211 NL S-Hertogenbosch, The Netherlands bMedical Department, Ciba-Geigy Ltd, Arnhem, The Netherlands ‘Drechtsteden Hospital, Zwijndrecht, The Netherlands ‘Hospital Gelderse Vallei, Wageningen. The Netherlands eDe Wever Hospital, Heerlen. The Netherlands fHospital Rijnstate. Arnhem, The Netherlands BThe Red Cross Hospital, The Hague, The Netherlands
Nieuwstraat
34,
Received 28 April 1994; accepted 24 November 1994
Abstract
Fifty postmenopausal womenrequiring hormonereplacementtherapy for the treatmentof climactericsymptoms were recruited in six centers.All patients receiveda new combinednorethisteroneacetate(NETA)/oestradiol (EJ‘ITS, (EstragestTTS, Ciba-GeigyLtd), delivering0.25mg NETA and 50 gg E, per day, continuouslyfor 12calendar months.Bleedingoccurredin 38 (76%)of the 50 patientsat any time during the 1 year treatment.The percentageof patientswithout bleedingincreasedgradually eachmonth, from 24% in the secondmonth to a relatively stablelevel of - 80%in month 7 and thereafter.Twenty-sevenpatients(54%)did not completethe wholetrial period; 15of which discontinuedthe treatmentwithin the tirst few monthsdueto irregularbleeding.In patientswho remainedin the trial, a clear decrease in the frequency and intensity of the bleedingwasobservedwith time. Bleedingwasmostly light or consistedof spotting only. None of the post-trial biopsiesshowedproliferation or hyperplasiaof the endometrium. The treatmentresultedin a substantialdecreaseof climactericsymptoms(Kuppermanindex) within 4 monthsand was well tolerated. It was concluded that the continuous NETA/E,-‘ITS the treatmentof climactericsymptomsin selectedpatients. Keywords:
l
Transdermal;
Postmenopausal
women; Continuous
treatment
oestrogen-progestogen
Corresponding author
0378-5122/95/$09.50 SSDI
0378-5
0 1995 Elsevier Science Ireland Ltd. All rights reserved
122(94)00891-A
is an effective and safe alternative
treatment
for
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et al. /Maturitas
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1. Introduction
2. Subjects and methods
An increasing number of women are currently using hormone replacement therapy (HRT) to alleviate climacteric symptoms [l] or in the prevention of postmenopausal osteoporosis [2]. In order to avoid the risk of endometrial cancer, the oestrogen treatment should be combined with progestogen administration [3]. Most regimens use sequential oestrogemprogestogen combinations, which result in a regular withdrawal bleeding in the majority of women. Bleeding is disliked by most patients and can lead to problems with compliance [4]. Oral continuous combined oestrogenlprogestogen treatments, in which the oestrogen and progestogen are given daily, have been tried in various dosages and these regimens produce amenorrhoea in several patients (up to 70%) within a few months [S-14]. Side effects that were encountered with this type of therapy have been irregular bleeding, especially during the first few months, and unwanted physical and psychological problems from the progestogen. Transdermal treatment with a norethisterone acetate (NETA)/estradiol (E,)-TTS (Estragest TTS, Ciba-Geigy Ltd) delivering 0.25 mg NETA and 50 pg E2 per day, in sequence with Estraderm TTS 50 has been established to be efficacious in the control of menopausal symptoms and of bleeding, and in the prevention of endometrial hyperplasia [15-181. The same combined NETA/E,-TTS was used in small single center studies using a continuous schedule [19-211. Although initial bleeding was relatively frequent, this improved rapidly during the first 6 months and further during the extension period. It appeared that patients who had not experienced any bleeding for a prolonged period prior to starting the therapy had a higher chance of remaining amenorrhoic, while no endometrial anomalies were detected. The present trial was designed to evaluate the effects of the continuous combined treatment of NETA/E?-TTS in a larger number of patients with regard to the occurrence and intensity of uterine bleeding as well as on endometrial histology after 12 months treatment.
The trial was designed as an open noncomparative, multicenter trial. After approval of the responsible ethical review boards, written informed consent was obtained from each eligible patient entering the study. 2.1. Patients Fifty healthy postmenopausal patients requiring oestrogen replacement therapy for treatment of climacteric symptoms were recruited in six centers. At enrolment, the patients either had the last menstrual bleeding more than 12 months ago, no previous hormone replacement therapy and a negative gestagen challenge test (10 days 10 mg medroxyprogesterone-acetate (MPA)), or previous oestrogen and sequential gestagen therapy with regular or no withdrawal bleeding episodes at the end of the gestagen treatment period. The last treatment dose should have been given more than 14 days prior to the start of trial treatment. If the gestagen challenge test resulted in bleeding, an endometrial biopsy had to be performed, which should have been normal. At the first visit the eligibility of a patient for the trial was assessed on the basis of the medicaYgynaecologica1 history and a full physical examination. A mammography, if not performed during the previous year, was carried out. Menopausal symptoms were evaluated by the Kupperman index [22], ranging from 0 to 51, and the trial procedure was explained. 2.2. Methods Two weeks after the initial visit, the Kupperman index was repeated and any bleeding events of the previous period were recorded. If the Kupperman index was 14 or more, the patients received diaries and trial medication for 3 months. Patients received calender packs, each containing 10 combined NETA/E,-TTS (Estragest TTS, Ciba-Geigy Ltd), delivering 0.25 mg NETA and 50 pg E2 per day, to be replaced every 3 or 4 days. Eight or nine patches were required per month. The remaining patches were kept as spares, and used when patches came off and could not be reapplied.
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Table 1 Patient characteristics recorded at first visit (n = 50)
Age
Mean Standard deviation Range
Height (cm)
Weight (kg)
Blood pressure (mmHg) Systolic
Diastolic
Months since LMP
Duration of menopausal symptoms (months)
50.9 4.9
166.5 6.5
64.3 8.1
130 13
79 9
47.8 32.0
45.6 30.0
34-59
152-180
50-83
90-170
50-95
S-144
9-144
LMP, last menstrual period.
In the 3rd or 4th treatment month, and again in the 6th or 7th month, the patient’s diaries were examined and any adverse experiences, changes in concomitant disease and medication were recorded while the Kuppennan index was repeated. Medication and diaries for the following period were supplied. At the last visit, after 12 months of treatment a full physical and gynaecological examination was performed. An endometrial biopsy (VABRA or comparable technique) was performed and all samples were evaluated by a pathology laboratory according to the following categories: inadequate for assessment, atrophic, proliferative (presence of one or more mitoses), hyperplasia (cystic or adenomatous, simple or atypical), secretory (secretory granulae) and non-secretory (no mitoses, no secretory granulae). The frequency, intensity and duration of vaginal bleeding during the 12 months was recorded in the patient’s diary. The number of bleeding episodes (i.e. a continuous sequence of bleeding days interrupted by no more than 1 bleeding free day), the total number of days of bleeding and the number of days of different intensity, per treatment month, were determined. The patient was asked to rate skin tolerability and adhesion and at each visit the skin application sites were examined by the physician. 2.3. Statistical methods The study population and the effects of therapy are presented by descriptive statistics. For the
Kupperman index, blood pressure and weight an end-point analysis (last available assessment compared to baseline) was performed. 3. Results
3.1. Patient characteristics The characteristics of the patients are shown in Table 1. With a mean age of 5 1 and a menopausal age of - 4 years these women had a relatively early menopause. At the start of the trial patients who would discontinue trial treatment prematurely were, on average, more than 6 kg heavier than patients who completed trial treatment (67.2 vs. 60.9 kg). The distribution of the patients over previous hormonal therapy and menopausal age is given in Table 2. Except for one patient (mastopathy) all mammography findings were normal. In total, 38 paTable 2 Distribution of patients over previous hormonal therapy and menopausal age Years since menopause l-38 Previous hormonal therapy 14 No Yes 10 Total 24 %cluding
>3-5
>5
4 8 12
7 7 14
Total
25 25 50
one patient who was 5 months postmenopausal.
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b
1
2
3
4 5 6 7 6 Month oftialtreatment
910
1112
1234567 Monthoftlfaitr6atm6nt
EpkocbscJ0E31~2iB2Y3~4~5
Epbod8snoel6sTiiJ2m2Y3~4~5 -
Numbrontopufbarismeannumberof@sodesperpaU6nt
Nmbarontopdbarlamaannumberd~perpelient
16
16 C
I4
14
12
12
8$1
f l'tl
0
0
%
42
r
0 1
2
3
4
5
6
7
6
Q 10
11 12
6llgMl%?aMcdllNn-m
42
i
0 1234567
MonthdW-
MmMhdbld~
6walnyzc76pd6nQ~
s
60verl&O6pdIhQ~
3ngMaasarMadllml-6tmnQ
Fig. 1. (a) Bleeding episodes per month for completed patients; (b) bleeding episodes per month for discontinued patients; (c) mean number of days with bleeding per month for completed patients; (d) mean number of days with bleeding per month for discontinued patients.
tients underwent an MPA challenge test. Four of them experienced a short bleeding of l-5 days duration which began 4-14 days after the start of MPA. In total, six endometrial biopsies were performed prior to treatment, which all proved to be atrophic. 3.2, Premature discontinuation Twenty-seven patients (54%) did not complete the whole study period; the treatment duration of
these patients ranged from 10 to 237 days. The main reason for discontinuing treatment was poor tolerability (n = 19), including unsatisfactory therapeutic effect (n = 4). Fifteen patients mentioned bleeding problems among the reasons for discontinuation of treatment. In six patients, local tolerability problems caused discontinuation of the trial medication. In one patient unsatisfactory therapeutic effect was mentioned as the only cause for discontinuation. One patient had to stop treat-
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.~ 4
A--
5
6
7
8
9
L
10
11
12
months
Fig. 2. The percentage of patients without bleeding per month ( -.-.-) related to patients in study; ( - + -) related to all patients started.
ment due to hypertension, which was already present before the start of the trial. 3.3, Occurrence of bleeding
Bleeding at any time occurred in 38 patients (76%), of which 16 patients (32%) completed the trial and 22 patients (44%) discontinued treatment prematurely. For twelve patients (24%) no bleeding was reported during the whole treatment period, of which 7 (14%) completed the trial. 3.4. Bleeding episodes,days and intensity
The mean number of bleeding episodes per treatment month decreased gradually from 0.9 (month 2) to 0.2 (month 12) for completing patients (Fig. la), and ranged from 0.9 (month 5) to
2.1 (month 4) for discontinuing patients without an improvement over time (Fig. lb). The number of patients who completed the trial with no bleeding episodes increased markedly from 9 (39%) in the first 2 months of treatment to about 18 (78%) after 6 months of treatment (Fig. la). The mean number of days with blood loss per treatment month gradually decreased and ranged from 3.9 (month 2) to 0.2 (month 12) for completing patients (Fig. lc). Also, for discontinuing patients an improvement was observed (Fig. Id) from 14.5 (month 2) to 9.1 (month 6). This was most probably due to discontinuation of heavy bleeders. Most of the bleeding in completing patients consisted of spotting (44%) or slight bleeding (40%), while strong bleeding occurred only once, for a period of 2 days in the third month of trial treatment. In addition, most of the bleeding consisted of spotting (47%) or slight bleeding (36%) for discontinuing patients. The percentage of patients without bleeding in any one month increased gradually, from 24% in the second month of treatment to a relatively stable level of about 800/o (fluctuating within a range of - 10%) in the 7th month and thereafter (Fig. 2). The increase reflects both the discontinuation of patients with frequent bleeding as well as the improvement in completing patients. The percentage of patients without bleeding in any one month related to the 50 patients who started the study only slightly increased from 28% in the first treatment month to 42% in the 7th treatment month, whereafter a stabilization to 36% was observed. It
Table 3 Patients categorized according to bleeding pattern No. of patients Trial completed PDa
Never bled or in one month only Bled every month or except in one month Mixed pattern
Reason for PD Bleeding as bleeding Month l-6
Month 7-12
13
8
5
0
I
0
22
2
20
15
22
6b
15
13
2
0
15
5
aPremature discontinuation; bmost of the patients discontinued during the first 6 months.
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Table 4 Endometrial biopsies, amount and histology at the end of treatment Biopsy material
Histology
Total None Small Moderate no. of obtained amount amount biopsies Non-bleeding patients Bleeding patients All
Abundant amount
Inadequate for assessment
Atrophic
Proliferative
Hyper- Secre- Nonplasia tory secretory
6
1
5
0
0
6
0
0
0
0
0
23 29
2 3
20 25
1 1
0 0
13 19
8 8
0 0
0 0
0 0
2 2
appeared that among patients with a menopausal age of 3-5 years, more amenorrhoea (up to 75%) was observed than among patients with menopausal age less than 3 years or more than 5 years. Among patients with previous hormonal therapy there was also more amenorrhoea (up to 48%) observed than among patients without such therapy. Table 3 categorizes the patients into a group that never bled or bled in 1 month only, patients who bled every month or except in 1 month and those with a mixed pattern of bleeding, respectively. Patients who had amenorrhoea from the beginning of the therapy usually remained amenorrhoic. Most of the patients who bled every month during the first months discontinued the treatment before month 6 and almost all mentioned bleeding as the main reason for stopping the trial. Patients who only bled during some of the first months mostly continued treatment and showed amenorrhoea or a clear decrease of bleeding after the first 6 months. 3.5. Endometrial biopsies The results of the 29 biopsies performed at the end of the trial treatment period are summarized in Table 4. Post-trial biopsies were performed in 21 out of the 23 completing patients and in 8 out of the 27 discontinuing patients. No biopsy material was obtained in three patients. In the remaining 26 patients, only a small or moderate amount of material was obtained; 16 of these biopsies were inadequate for assessment, 8 were atrophic and 2
non-secretory. In patients who experienced bleeding during the study the biopsies were either inadequate for assessment (n = 13), atrophic (n = 8) or non-secretory (n = 2). There was no sign of endometrial hyperplasia or proliferative endometrium. 3.6. Kupperman index The mean total score of the Kupperman in&x, as recorded at visit 2 was 25.2 (range 8-42) for all patients, 26.8 (range 15-42) for completing patients and 23.8 (range 8-34) for discontinuing patients. One patient had a Kupperman score of only 8 at visit 2 and should have been excluded. A large decrease of the Kupperman index was observed during the first 4 months of the trial period, followed by a relatively stable period during which the score levelled around values of 8. In the end-point analysis a significant decrease (P < 0.001) was observed when compared to baseline. At the end of treatment the mean index was 8.1 (range O-25) for all patients, 7.1 (range O-25) for completing patients and 8.9 (range O-24) for discontinuing patients. 3.7. Systemic and local tolerability Mean body weight and systolic and diastolic blood pressure did not change (P > 0.10). On physical examination, no abnormal lindings occurred during the study period. Painful or tender breasts were reported by 5 patients. The majority of the patients, both discontinuing
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and completing the study, regarded the skin tolerability and adhesion as good to very good. Skin tolerability was judged as poor by seven patients, of whom only one completed the trial. The majority (72) of the IO!9 observations on the skin sites of the last patch applied revealed no traces of irritation. Erythema was noticed thirty times, swelling was observed four times, scales twice and papules once. No serious adverse events occurred during the study. 3.8. Compliance
Based on the number of used patches returned and the quality of the diaries compliance was judged as good. 4. Discus5ion
In this study the efficacy and tolerability of continuous combined treatment with NETA/E,-TTS (Estragest TTS) was investigated in an open nonrandomized design in 50 patients. The main parameters were the frequency, intensity and duration of bleeding, as well as the endometrial histology. Bleeding occurred in 38 (76%) of 50 patients at any time during the 1 year treatment. Both the duration as well as the intensity of bleeding decreased in time. Bleeding was mostly light or consisted of only spotting. Amenorrhoea became more frequent with time; this was preferentially due to discontinuation by bleeding patients, although a decrease was also observed in the completing patients. It was shown that patients who had amenorrhoea from the beginning of the therapy usually remained amenorrhoic. In 15 of the patients bleeding problems were mentioned among the reasons for premature discontinuation. The percentage of patients without bleeding in any one month related to all 50 patients who started the study increased only from 28% in the first treatment month to 42% in the 7th treatment month, with a subsequent stabilization to 36%. Our results seem to be slightly better than the recent findings with two oral regimens of continuous combined therapy [13], where one third of the women had amenorrhoea by week 78 of therapy, while 62% of the women had withdrawn mainly
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due to chronic bleeding. In contrast to this study, no dose adjustments were allowed in our study protocol. Compared to another study [12] using two oral continuous regimens our results are quite comparable. In the early studies with continuous combined therapy, higher percentages of amenorrhoea are found [5-81, due to the fact that withdrawals were not considered. Furthermore, those early studies were performed by one investigator, whereas our study took place in six centers with a very large inter-center variation with regard to the number of drop outs (range 25- 100%). Our patients were also relatively young (mean age 51 years) and it is known that younger patients have a higher risk of irregular bleeding with this type of treatment [5,6]. Various patient characteristics such as age, menopausal age, previous sequential therapy and weight seem to influence the bleeding pattern. Patients with previous hormonal treatment bled less frequently and shorter than patients without prior treatment. However, in other studies [13,20] patients who had received sequential therapy prior to continuous combined therapy had more bleeding. More amenorrhoea was observed in patients (n = 12) between 3 and 5 years postmenopausal than in patients with a menopausal age of less than 3 years (n = 24) or more than 5 years (n = 14). It has been repeatedly found [5,6] that older patients and patients with a menopausal age of a few years respond better to this type of treatment than perimenopausal women. The results in the 14 patients with a menopausal age of more than 5 years could be explained by accidentally more bleeding from an atrophic endometrium. At the start of the trial patients who would discontinue prematurely were, on average, more than 6 kg heavier than patients who completed the trial treatment. The same was found by Sporrong et al. [1 1] and could be explained by additional bleeding in this group as a result of a higher conversion of androgens into oestrogens in the subcutaneous adipose tissue. Different suggestions have been made to predict patients that will be amenorrhoic with continuous combined therapy [6,8,11,13]. However, the results of the different studies do not agree and there
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is no consensus as yet as to which patients have a high chance of becoming amenorrhoic. It is interesting that in another study [24] with transderma1 continuous combined therapy using a lower dose of NETA/Ez 0.125 mgl25 pg per day, almost no bleeding was observed in older (1 58 years) women. A greater counteractive effect of oestrogen stimulation of the endometrium by adding progestogens continuously was suggested earlier [20]. There was no sign of endometrial hyperplasia in the biopsies at the end of the trial treatment. All biopsies were either inadequate for assessment or atrophic except for two biopsies in the bleeding patients that were non-secretory. These results show that, comparable to oral regimens [9,10,13], the oestrogenic effect on the endometrium is well antagonized by the progestagen with transdermal continuous combined therapy. In the light of the two cases of adenocarcinoma of the endometrium found in a long-term follow-up study [23] in patients using oral conjugated oestrogens combined with norethindrone, careful follow-up of these patients is still required. However, before combined treatment was started one of these patients was on an unopposed regimen, while the other used a sequential regimen over a longer period. The Kupperman index dropped from 25.2 to 8.1, so the control of menopausal symptoms was adequate. This was to be expected as the amount of estradiol delivered per day is the same as with Estraderm TTS 50. General tolerability of the treatment was good. Neither blood pressure nor weight were altered. Besides bleeding problems, painful or tender breasts and dermatological problems were the most frequently reported side effects. The good compliance can partially be accounted for by the good tolerability. In most patients the judgement of skin tolerability and adhesion as well as the overall assessment of tolerability was regarded as very good to good. Of the 23 patients who completed the trial, seventeen were willing to receive the same therapy for further alleviation of their menopausal symptoms.
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5. Conclusions In this study it was shown that treatment with continuous combined estradiol/norethisterone acetate TTS (NETA/E2-‘ITS) can be expected to be as safe as oral hormonal combined replacement regimens. This type of treatment is especially suited for patients accepting the risk of irregular bleeding during the initial treatment period. Efficacy in the control of climacteric symptoms was good and was maintained during the whole trial. Systemic and local tolerability also proved to be good. The results of post-trial endometrial biopsies suggest that the treatment does not stimulate proliferation of the endometrium after 1 year treatment. Nevertheless, careful monitoring of endometrial development by, for example, ultrasound and/or regular endometrial sampling for histology, still seem to be mandatory in long-term combined treatment. Furthermore, phase 3 trials to characterize the population that is most suitable for this type of treatment and to investigate possible metabolic effects are ongoing. Acknowledgements The authors wish to thank H. Hollema, M.D. Ph.D., gynecopathologist, University Hospital of Groningen for his evaluation of the biopsies. The work of J.P.J.M. Pfeil, MSc, head statistical department, L.A.B. Benelux, Arnhem, The Netherlands is also greatly appreciated. Finally we thank Dr. L. Schenkel, Ciba-Geigy, Switzerland for her critical evaluation of the manuscript. References [I] Campbell S, Whitehead M. Oestrogen therapy and the menopause syndrome. Clin Obstet Gynaecol 1977; 4: 31-47.
[2] Weis NS, Ure CC, Ballard JH. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of oestrogen. N Eng J Med 1980; 303: 1195-g. [3] Whitehead MI, Townsend PT, Pryse-Davies J, Path FRC, Ryder TA, King RJB. Effects of estrogens and
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progestins on the biochemistry and morphology of the menopausal endometrium. N Engl J Med 1981; 305: 1599-605. [4] Ryan PJ, Harrison R, Blake GM, Fogelman I. Compliance with hormone replacement therapy after screening for postmenopausal osteoporosis. Br J Obstet Gynaecol 1992; 99: 325-8. [5] Staland B. Continuous treatment with natural oestrogens and progestogens. A method to avoid endometrial stimulation. Maturitas 1981; 3: 145-56. [6] Mattsson LA, Cullberg G, Samsioe G. Evaluation of a continuous oestrogen-progestogen regimen for climacteric complaints. Maturitas 1982; 4: 95-102. [7] Magos AL, Brincat M, Studd JWW, Wardle P, Schlesinger P, O’Dowd T. Amenorrhea and endometrial atrophy with continuous oral estrogen and progestagen therapy in postmenopausal women. Obstet Gynecol 1985; 65: 496-9. [S] Staland B. Continuous treatment with a combination of estrogen and gestagen - a way of avoiding endometrial stimulation. Acta Obstet Gynecol Stand 1985; Suppl. 130: 29-35. 191 Bewtra C, Kable WT, Gallagher JC. Endometrial histology and bleeding patterns in menopausal women treated with estrogen and continuous or cyclic progestogen. J Reprod Med 1988; 33: 205-8. [IO] Hovik P, Sundsbeck HP, Gaasemyr M, Sandvik L. Comparison of continuous and sequential oestrogenprogestogen treatment in women with climacteric symptoms. Maturitas 1989; 11: 75-82. [ 1I] Sporrong T, Samsioe G, Larsen S, Mattsson LA. A novel statistical approach to analysis of bleeding patterns during continuous hormone replacement therapy. Maturitas 1989; 11: 209-15. [12] Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous and sequential oestrogen-progestogen treatment in women with climacteric symptoms. Maturitas 1989; II: 75-82. [ 131 Hillard TC, Siddle NC, Whitehead MI, Fraser DI, PryseDavies J. Continuous combined conjugated equine estrogen-progestogen therapy: Effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis. Am J Obstet Gynecol 1992; 167: 1-7. (141 Obel EB, Munk-Jensen N, Svenstrup B et al. A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment. Maturitas 1993; 16: 13-21.
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[15] Schenkel L. Development of a combined estradiolnorethisterone acetate ‘ITS. In: Transdermal Hormone Replacement therapy. Eds. Whitehead MI and Schenkel L. Camforth UK: Parthenon Publishing, 1988; 59-65. [16] Whitehead MI, Fraser D, Schenkel L, Crook D, Stevenson JC. Transdetmal administration of oestrogen/progestagen hormone replacement therapy. Lancet 1990; 335: 310-2. [17] Gangar K. Endometrial histology and bleeding patterns during administration of continuous oestradiol and sequential transdermal norethisterone acetate. In: Whitehead MI, Schenkel L, eds. Transdermal Hormone Replacement Therapy. Long-term Effects. Camforth: Parthenon Publishing, 1990; 67-70. [18] Lindgren R, Risberg B, Hammar M, Berg G, PryseDavies J. Endometrial effects of transdermal estradiohnorethisterone acetate. Maturitas 1992; 15: 71-8. [19] Uvebrant M. Continuous transdermal administration of combined oestrogen/progestogen for climacteric symptoms. Presented at the Sixth International Congress on the Menopause, Bangkok, Thailand, 1990. Abstracts. Camforth: Parthenon Publishing, 1990; Abstr. 247: 251. [20] Schenkel L, Hillard TC, Fraser D, Ellerington M, Whitehead MI. Transdermal continuous combined oestrogetigestagen therapy: development of amenorrhoea over 18 months. Int J Gynecol Obstet. Abstracts. XIII World Congress of Gynaecology and Obstetrics (FIGG), Singapore, 1991. Abstr. 1198. [21] Keller PJ, Hotz E, Imthurn B. A transdennal regimen for continuous combined hormone replacement therapy in the menopause. Maturitas 1992; 15: 195-8. [22] Kupperman HS, Blatt MHG, Wiesbader H, Filler W. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrhea] indices. Endocrinology 1953; 13: 688-703. [23] Leather AT, Sawas M, Studd JWW. Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women. Obstet Gynecol 1991; 78: 1008-10. [24] Hillard T, Ellerington M, Whitcroft S, Godvree V, PryseDavies J, Whitehead MI. The effect of low dose transderma1 continuous combined oestrogen and progestogen on breast tenderness, vaginal bleeding and endometrial stimulation. An ideal treatment for the “older” woman? Presented at the Sixth International Congress on the Menopause, Bangkok, Thailand, 1990. Abstracts. Camforth: Parthenon Publishing, 1990; 91, Abstr. 87.