Evaluation of a continuous oestrogen-progestogen regimen for climacteric complaints

9s

Mafurim~, 4 (1982) 95-102 Elsevier Biomedical Press

Evaluation of a continuous oestrogen-progestogen regimen for climacteric complaints L.-A. Mattsson ‘.*, G. Cullberg ’ and G. Samsioe’

Subjective wmplainls, cndomelrial bistopathology. vaginal cytology and bleeding patterns were recorded in 26 patients treated with d mnlinuous owrogcn-progestow~ re&nsn for I2 mth. A marked reduction ot hoc flushes and sweats were noted and the evaluation ot cndomettial spccimena revealed thrill the mwosae were mealy inactive-atrophic. The karyopyknotic index proved to be a poor indicator of oescro,genic activily. The number of recorded bleedings in the psri-menopausal women dittered markedly Iran the pon.mcwpausal women during treatment: they were very slighl in the kitler group. Even in those EPEC~where bladiig oc~urrcd. Ihe endometrial samples were found to be atrophic. Vaginal bleeding wemcd to be an unreliable indicator of cndometrial histopathology. The present combination of hormonea used in a wnlinuous regimen is a good alternative for posl-menopausal women in need of homwmal therapy. (Key words: Climacteric

sy.npwns.

Oesaogens.

Progestogens)

Many women experience climacteric symptoms such as hot flushes and sweats around the menopause, especially within the first 12 mth after the menopause [l]. Relieving these climacteric complaints by replacement therapy with sex steroids has been well documented. Compared to placebo oestrogens as well as progestogens have been reported to be effective [i-4]. The regimens most often used comprise different hormone sequences for 3 wk followed by 1WSwithout treatment. A common complaint amongst users is that the symptoms return during the week in which no tablets are taken. B&in and Staland [5] have reported a recurrence of symptoms if the oescrogen intermission is more than 3 or 4 days. Since 1975 increased attention has been focused on unopposed oestrogen replacement therapy given to post-menopausal women and its connection with adenocareinoma of the endometrium. A reduction of hyperplasia has been reported to occur with the addition of pro&estogens to the oestrogen therapy [C,7]. The incidence of corpus malignancy occurring in oestrogen-progestogen users has been shown to be even lower than that observed in untreated women IS]. Sturdee et al. (91 proposed -* To

whom rcprin( xq,csts

should be addressed.

0378-5 l22/82/CWJO-WOO/SO2.75

0 1982 Elsevier Biomedical

Press

% that progestogens should be taken for at least 10 to 13 days during the cycle in order to guarantee a ‘healthy’ endometrium. The aim of this study was to evaluate the clinical and morphological effects of an oestrogen-progcstogen therapy administered continuously instead of cyclically to peri- and post-menopausal women with climacteric complaints.

Materfal and m&n& Putients and drug administration

At the start of this study, 28 women ;Yere included who had sought help at the gynaecological out-patient clinic of East Hospital in Gothenburg for their climacteric complaints. These women were either peri- or post-menopausal. The latter group of women experienced their last menstrual bleeding at least 4 mth prior to the study. Before treatment, the mean age of the peri-menopausal women was 47.7 yr and that of the post-menopausal women, 52.8 yr. The time after the last menstrual bleeding in both grotips was 2.6 and 22.2 mtk respectively. All patients participated in the study after informed consent. The Ethical Committee of Gothenburg University approved the design of the study. A combined ocstrogen/progestogen therapy was administered in a continuous regimen for 1 yr. Each tablet, ingested daily, consisted of 2 mg I’l~oestradiol, 1 mg oestriol and I mg norethisterone acetate (Klimagen, NOVO. Denmark). No other hormones or drugs were taken for at least 4 wk prior to the study. Of the 28 women who started the treatment, 2 dropped out in the beginning. One of these 2 women withdrew after 3 wk of treatment because of heavy bleeding. This woman had had an endometrial curettage performed 3 wk prior to the study because of menorrhagia. The histological examination of her endometrium revealed cystic hyperplasia. The second patient dropped out because she left the area. One other woman discontinued treatment after 10 mth because she experienced depressive symptoms, She was referred to a psychiatrist and was later treated with antidepressive drugs. The 26 participants who did remain in the study ranged in age from 43 to 59 yr (a = 50.3). I1 of whom were peri-menopausal and I5 were post-menopausal. The observation period totaled 310 treatment months. Design of the study The women were examined and blood samples were obtained before treatment then 3 mth after treatment started, and again at the end of treatment (12 mth). At each examination, the following parameters were stndied. (1) A general physical examination including blood pressure and body weight measurements was performed. (2) A gynaecological examination, including vaginal cytology, was performed at each visit. Endometrial curettage was performed after 3 mth. In cases of bleeding

97

disturbances, another curetiage was performed at the end of the study after 1yr. (3) For 3 days prior IO each examination, every patient recorded climacteric complaints and side effects. A special form for recording the frequency and duration of spottings and break-through bleedings was used throughout the treatment period. (4) Liver function tests (bilirubin, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase) were performed. Methods Endometrial biopsies were obtained with Randall’s cureue under local anaesthesia (Xylocaine’. Astra. 1% without epinephrine) administered as a paracervical block. These biopsies were fixed in neutral formalin, embedded in paraffin and sectioned at s.:veral levels. Sections were stained according to Van Gieson. All biopsies were examined by one pathologist for signs of hormonal effects and atypia. Vagina/ cyrology was studied after specimens were taken from the lateral fornix and stained according to Papanicolaou’s technique. All specimens were examined by one cytologist who used the percentage of superficial cells, i.e. the karyopyknotic index (KPI), as a measurement of oestrogenic influence.

Clinical series

After 3 mth of treatment 23 out of the 26 women were completely free from vasomotor disturbances as indicated from their individual recordings. After 12 mth of treatment, the figure dropped to 22 out of 26. Those who still reported some sweating experienced them only slightly (Fig. 1). No significant changes were found in body weight, blood pressure or liver function. Concerning side e/j&s. Mastalgia was experienced by 4 women and increased irritabibty by 9 - both within the first period of treatment, Intermittent headaches were a problem for 6 women, 2 of whom also experienced depressive symptoms. An extensive increase in uterine fibroid growth was noted in 2 women after 1 yr of treatment. In both cases the size of the uterus corresponded 1.0 that of a pregnant uterus of about 14 wk gestation. A regress to almost normal uterine size was found 3 to 4 mth after discontinuation of treatment in both cases. Registration

of

bleeding

During treatment, the duration of bleeding gradually decreased (Pig. 2). Breakthrough bleedings occurred most frequently during the first 3 mth. The bleedings were reported by most women as being slight and of minor discomfort. A difference in bleeding frequency was observed between the peri- and the post-menopausal groups of women. In the group of 11 peri-menopausal women one had no bleeding at all. Bleedings were not experienced in I1 out of the IS post-menopausal women,

Fig. 1. Total number of hoc flurbcs and sweats recorded by the post.menopawl (m) and p&menopausal (Cl) women for 3 days prior to each exmnitwion: before treatment started. rben after 3 and 12 mth.

with the exception of very sparse bleedings in the beginning of treatment. The differences in the amount of days in which all women experienced bleeding became more evident throughout the treatment period (Table I). Morphology

After 3 mth of treatment, endometrial biopsies were taken from a!1 women. Specimens were often difficult to obtain probably because of a thin endometrium. There were no systematic differences noted in the endometrial morphology between the peri- and post-menopausal women. The bistopathological findings from all women are shown in Table II. In most women the mucosa was inactive-mrophic.

!l P

Fig. 2. Comparison of lbc number of days with ble&iag pa patient behvan the pert- and post-menopauul

I yr

groups during of ocstrc$enmcnopnusel group of UOlncIl.

tre%tmmtc. 0 =pai-~wwl

gm!Jp of WBnen:

l =porc-

TABLE I FREQUENCY OF BLEEDING (DAYS) THROUGHOUT CONTINUOUS OESTROGEN/PROGESTGGEN TREATMENT IN PERI- AND POST-MENOPAUSAL WOMEN. Treatment period

Days with bleeding

(mth)

I-III IV-VI VII-IX X-XII

Peri-menopausal w0men (n=ll)

Post-menopausai wumen (,I = IS)

l&/Y24 (18W, n/924 (8%) V/Y24 (6%) 68/868 (8%)

186/1260 (15%) 7K/ I260 (6%) 34,‘1260 (3%) IS,‘1260 (I%)

In 8 women who experienced bleeding dist.ubances during the last 3 mth of treatment a second curettage was performed (Table 11). No hyperplasia or malignancy was detected in any of these 8 specimens.

Specimens take before treatment and after 3 and 12 mth of treatment were evaluated for the karyopyknotic index. Slight differences were found in both the pre-treatment and treatment values between the peri- and post-menopausal groups of women. The mean KP! before, during and after treatment appear in Table II. There was a wide variation and no significant differences were found. Hormonal influence was impossible to evaluate in many samples before treatment due to inflammation. A change took place in the Pap smear of one woman during the treatment. At the 3 mth examination, cell atypia grade II was present and at a later control. there was a further change to grade III. An excision from the cervix revealed a moderate

TABLE II HISTOPATHOLOGICAL DIAONO~IS AND KPI OF 26 WOMEN DURING OESTROGEN-PRGGESTOGEN TREATMENT OVER A I2 mth PERIOD. Trcwwnt periods (mth)

7 Histopnthologicaldi~gnosrs (no. of women)

12

KPI (%)

11.8-cI6.0

0 3

A CONTINUOUS

hutetive-atrophic ecrpusInucOSa (17) Sparse currettagc,mostly surface rpithelium(8) CorpusIIIUCOS~ in desquemation (I)

15.4214.9

Atrophic mwosa (5) Muwm with signs of OC treatment (2)

20.0~ 15.6

Corpus mwosa in desquunation (I)

dysplasia to which cryosurgery was performed. A cell atypia grade. III was still present when the third smear was taken. The patient was then treated with conization of the cervix; after which, stage I was retained and stabilized. Diwsion

During the time around the menopause, many women experience different symptoms of both psychological and physical character. Most of these symptoms have been attributed to a decrease in ovarian activity, although it has not been determined exactly which symptoms are due to oestrogen deficiency. According to prospective placebo controlled trials by Utian [lOI and Campbell and Whitehead [I l], the only true direct hormone related changes which occur in either surgical or natural menopause were those of hot flushes, sweats and vaginal dryness. Several investigatorr have reported on the relief of subjective symptoms during oestrogen therapy. In 1975, Bullock et al. [3] reported on the relief of vasomotor symptoms in a group of peri-menopausal patients receiving depo-medroxyprogesterone acetate. In comparative studies, Dennerstein et al. [4] found that norgestrel was preferred to a placebo in reducing hot flushes, although the effect of oestrogens in this respect was more otdspoken. A placebo preparation was not used in this study. It was evident, however, that the oestrogen/progestogen treatment had a good effect on the vasomotor symptoms. Since oestrogcns and progestogens have been known 12-41 to alleviate climacteric complaints, it could be speculated whether or no: the sex stiroids used in this preparation produced a synergistic effect on vasomotor parameters. Oestrogen activity is often assessed by calculating the percentage of superficial cells in a cytological smear. However, the results are often difficult to interpret when other sex steroids are administered together with oestrogen. A slight increase of the KPI was found during the treatment period in the present study. However, the KPI appeared to be a poor indicator of oestrogenic activity as it was probably influenced by a progestogen with possible anti-oestrogenic effects. We have found few reports on women’s attitudes towards bleeding in the periand post-menopausal period. One study, which reported results from a questionnaire, indicated that only a small portion of women approaching their menopause would feel sony when they no longer had menstrual periods [l]. There are no data available showing women’s opinion to withdrawal bleedings when oestrogen therapy is given. However, Lind et al. [12] reported that most women on such therapy would prefer not to have withdrawal bleediigs if there was an alternative. About 3040% of women treated with unopposed ocstrogens reported withdrawal bleedings (13,141.The corresponding frequency for withdrawal bleedings after an oestrogen-progestogen treatment was more than 90% 1151.In the present study, 64% of the peri-menopausal and 27% of the post-menopausal patients reported spottings or break-through bleedings during the third month of treatment. This figure de creased to about 40 and 136, respectively, during the last month of treatment. The marked difference between the peri- and post-menopausal grcups of women became

101

more evident throughout the treatment period. Only a few d:;ys of bleeding disturbances were reported by the post-menopausal women after the initial treatment. In the post-menopausal group of women about 80% of the days with bleeding were reported by three women. When considering withdrawal bleeding, it seems to be essential for the peri- and post-menopausal women to have different treatments. The reason for this is probably due to a variable endogenous hormone production. The post-menopausal women in this study were better suited to the continuous oestrogen/progestogen treatment used, since a reduced frequency and volume of endometrial shedding was achieved. This treatment would probably he favourahle for many women in need of sex hormone therapy. Most women said they would prefer a light bleeding 2 or 3 times a year (even if unpredictable) to a heavier regular shedding, provided the risk of endometrial hyperplasia is not increased. Some post-menopausal women have an increased risk for developing endometrial carcinoma. The probable explanation in these cases is an increased peripheral con.*ersion of androstenedione to oestrone, enhanced (for example) by obesity 1161. The cumulative risk for a patient with hyperplasia to develop endometrial carcinoma was found to be about 30% over a IO-yr period [I?). Increased attention has been paid to endometrial histopathology during various types of oestrogen therapy. In prospective, longitudinal trials the possibility of reducing endometrial hyperplasia by adding a progestogen to the oestrogen treatment has been emphasized. Gambrel1 et al. [S] found a reversal from hyperplasia to a normal endometrium in 242 out of 258 patients (93.8%) following a progestogen treatment period. Periodic endometrial shedding has been considered essential in avoiding endometrial hyperplasia. Also emphasized was that the duration of treatment is of greater importance than the dose of progestogens used and that Cl9 progestogens might be the most effective [9]. Whitehead (pens. comm.) reported that a lower dose of progestogens, from what is commonly used, is adequate in reducing the number of oestrogen receptors in the endometrium, in increasing the concentration of 17fl-o&radio1 dehydrogenase and in decreasing the DNA activity of the nucleus. The present combination of hormones used (oestrogen with progestogen) in a low continuous dose resulted in an atrophic endometrium after 3 ml of treatment. The low number of patients and the short observation period did not enable us to conclude whether the incidence of endometrial hyperplasia or cancer is decreased because of this regimen. It is therefore necessary to continue investigations on the necessity of inducing periodic withdrawal bleedings in order to achieve a healthy endometrium. The common complaint of recurring climacteric symptoms from patients on cyclical therapy was avoided by using a continuous regimen, In comparison with conventional schedules of treatment in which progestogens are given for 10 to 13 days every ‘cycle’, the total dose in the present combination was lower. From a metabolic Point of view this lower dose of the progestogen could be favourable.

102

Thanks are due to Assistart Professor Folke Knutsson for evaluation of the cndometrial specimens and Olaf Eriksson, M.D., for the evaluation of vaginal cytology. Klimagen was kindly supplied by NOVO Induswi A/S, Denmark. Thanks are due also to Mrs. Berit JohPnsson for typing the manuscript.

I Ma&inlay. SM. and Jcffcrys, M. (1974) The menopauul syndrome. Br. J. Prev. Sot. Med. 2X. 108-I IS. 2 Callamine. MR.. Martin, P.L.. B&ding O.T.. Warner. P.O. and Greaney. MO. (1975) Micronized I7#9.esImdidfor oral atroyo cblxapy in menupausalwalIen. Obnet. Gynocal. 46.37-41. 3 Bullock. J.L.. Massey, M.7, and GambrelI. R.D. (1975) Use of medroxyproges~~roncacetate to prevent rnen~pausalsymplomf..Obswt. Gynoal. 46, 165-168. 4 Dcmrrlcin. L., Burmws, G.D., Hyman, G. and Wmd. C. (197!3)Menopausalhog flushes: a double blind comparison of placebo. clhinyl oauadii and nqc.strel. Br. 1. ObsteI. Gynaecol. 85.852-856. 5 Bo@in. NE. and Slaland. B. (1975) Oral trcalmenlof menopausalsymploms with naturalocstrogenr. Acfd Obst$t. Gjnccol. Sand.. Sup~l.43. l-11. 6 Campbell. S.. Minardi, J.. M&Queen,J. and Wbitcbead. MI. (1978) Tlte modifying effect of progeuoya on the rewomc of the pos~mencpausalendomctriumIOcxogcnaus estrogens. Postgrad. Med. J. 54. SuppI. 2, E-64. 7 Pasrson. M.E.L., WstuEvans, T.. sCu&e, D.W.. llwm. M.H. and Swdd. J.W.W. (1980) EndcmcwiPi disease after treatmentwith oest-r and proyrtogcnr in the climacteric.Br. Med. J. 280. 822-824. 8 GambrelI,Jr., R.D.. Massey. F.M..CastPnodpT.A., Ugenas.A.J.. R&i, C.A.and Wright,J.M.(1980) Use of the progcstogm challeny test to redduecthe risk of mdomwial cancer. Obstet. Gyncwl., 55. 732-738. 9 Sturdec,D.W.. Wade-Evans,T.. Pawnon. M.E.L.. Tbom. M. and Studd. J.W.W. (1978) Relations beware bkeding pattern, endometrialbistiogy, and ogtrogen lreatmentin menopauul women. Br. Med. J. 1, 1575-1577. 10 UIha. N.H. (1972) Tbe tmc clinicalfeaturesof poslmcampauseand mphoreclomy and their response to oestro&x~therapy. S. Afr. Med. J. 46.732-738. 1I Campbell,S.. and Whitebead, M. (1977) Gcslrogcn lherapy and Ihc menopausalsyndrome. In: Clinics in Obstelriu and Gynaecology. vol. 4. pp. 31-48. Editors: R.G. Cwcnblatl and J.W.W. Studd. W.B. Saunders. London. I2 Lind. T.. Camerma,EC.. Hunter. W.M.. Leon, C.. Moran. P.F.. OxIcy. A., Gerard. J. and Lind. U.C.G. (1979) A prospective, comrolled lrial of six forms of hormone replacement~berapyriven to postmc~np~usalwomm. Br. 1. Obrwt. Gyna.xol. 86. Sup~l. 3. l-29. 13 Martin P.L.. Burn& A.M. and Greancy. M.G. (1972) Oral menopausal tbcmpy usinS 17-P micronizcd eswadiol. Obrtet. Gynecd. 39.771-774. 14 GambrelI. Jr.. R.D. (1978) The prcventicnof cndometrialcancer in postamopauul women with progatoyns. Maturitas I, 107-112. 15 Gambrel&Jr., R.D. (1977) Postmenopausalbleeding. In: Clinics in obstetrics and gynawdo8y. vol. 4. pp. !29-143. Editors: RG. SranbWt and J.W.W. Sludd. W.B. Saundm. Iandon. 16 MacDonald. P.C., Edman. C.D., Hemsell. D.L., Porter, J.C. and Siiti. P.K. (1978) Effccl of obaily on conversion of plasma andros~ to csuonc on p.xwwpati women wilh and witbout cndometrisl -. Am. J. Obstet. Gynecol. 130,44S-455. 17 Gusber&58. and Kaplan, A.L. (1963) Precursorsof corpus cancer. IV. Adenmnalous hyperplasiaas stage 0 carcinoma.Am. J. Obste~.Gyaccd. 135,947-956.