- Email: [email protected]
A new combination of conjugated equine oestrogens and medroxyprogesterone for treatment of climacteric complaints
Maturitas, 6 (1984) 55-63 Elsevier
MAT 0031
55
I
A new combination of conjugated equine oestrogens and medroxyprogesterone for treatment of climacteric complaints G. Cullberg I, F. Knutsson * and L.-k Mattsson ’ ’Department of Obstetrics and Gynaecology, University of Gijteborg, East Hospital, Giiteborg, Sweden; and ’ Department
of
Pathology, University of Gijteborg, Sahlgren S Hospital, Gijteborg, Sweden
(Received
7 November
1983; accepted
after revision
17 April 1984)
Thirty-four post-menopausal women with climacteric complaints were given conjugated equine oestrogens (1.25 mg/day) for 21 days followed by 2 days without hormones and then 5 mg medroxyprogesteroneacetate daily for 5 days. The present trial was designed to study effects on vasomotor symptoms, bleeding patterns and endometrial histopathology. Vasomotor disturbances were completely relieved. No recurrence of symptoms was recorded in the oestrogen-free week. Withdrawal bleedings were regular and slight, which was a positive experience for those women who had previously been treated with other oestrogen-progestogen regimens. In most patients inactive or weak secretory endometrial epithelium was found during treatment. Two women developed differing degrees of hyperplasia after 2.5, and 3 yr, respectively. This fact emphasizes the necessity of adding progestogens for at least 10 days each month even if the oestrogens and progestogens are administered separately. It may also be wise to perform an endometrial biopsy when sex hormones are administered on a long-term basis. (Key words:
Postmenopause,
Conjugated
oestrogens,
Medroxyprogesteroneacetate,
Endometrium)
After the menopause many women experience complaints of vasomotor origin. Both oestrogens and progestogens have been shown to alleviate such symptoms. However, a number of side effects, including endometrial cancer, has been attributed to unopposed oestrogen therapy [1,2]. In recent years combinations of oestrogens and progestogens have been advocated in order to avoid endometrial hyperplasia. Epidemiological and histological studies have shown that the addition of progestogens for at least 10 days every month will protect against hyperplasia and malignant degeneration of the endometrium [3,4]. It has also been reported from biochemical studies of the endometrium that lower dosages of progestogens than those commonly used today could be effective in suppressing effects on the endometrium induced by oestrogens [5].
Reprint requests to; G&an Cullberg S-416 85 Gateborg, Sweden.
03785122/84/$03.00
M.D.,
Department
0 1984 Elsevier Science Publishers
of Obstetrics
B.V.
and Gynaecology,
East Hospital.
56
Cyclical hormone replacement therapy (HRT) is widely used for the treatment of climacteric complaints, but some women experience a recurrence of symptoms in the tablet-free week [6]. Inevitably most patients treated with progestogens for 10 days or more on a monthly basis will experience a withdrawal bleeding which can be abundant and annoying. In an attempt to minimize the number of withdrawal bleedings a sequence combination of conjugated equine oestrogens (CE) and medroxyprogesteroneacetate (MPA) was evaluated. MPA was chosen as the progestogen supplement because of the reported favourable effect on vasomotor symptoms [7,8] as well as evidence that this progestogen may be more inert than the 19-nortestosterone derivatives where lipid metabolism is concerned [9,10]. The present study was undertaken to evaluate the clinical and morphological effects on a long-term basis of a new sequential oestrogen-progestogen treatment for post-menopausal women.
Material and Methods Patients and hormone replacement
therapy
Thirty-four patients with climacteric complaints, mean age 55 yr (range 47-63) were included in the study. They were all post-menopausal and the mean time after the last menstruation was 3.3 yr (range l-11). Their post-menopausal status was verified by analysis of follicle-stimulating hormone in serum (FSH) assessed by a radioimmunoassay method [ll]. Approval for the study was obtained from the Ethics Committee, Faculty of Medicine, University of Goteborg and all the patients gave their informed consent. Conjugated equine oestrogens, 1.25 mg, were given as a single daily dose for 21 days. After 2 days without hormones a 5 mg medroxyprogesterone acetate tablet was given daily for 5 days and the sequence was then repeated. Treatment was planned to continue for 3 yr. Design of the study Examination of the patients was performed before treatment, 6 and 18 mth after and then 3 yr after the start of treatment, or in between in cases of bleeding disturbances. FSH was analysed before and at the control examination after 6 mth. A general physical examination, including blood pressure and body weight measurements, were performed at each visit. Endometrial biopsies were taken on the last day of the MPA tablet administration after 6 and 36 mth of treatment. They were obtained with Randall’s curette under local anaesthesia (Xylocain, Astra 1% without epinephrine) administered as a paracervical block. In addition, a curettage was performed in 8 patients after 21 days of CE in the first treatment cycle. The biopsies were fixed in neutral formalin, embedded in paraffin and sectioned at several levels. Sections were stained according to Van Gieson. All biopsies were examined by one pathologist (FW
57
Bleeding patterns and side effects were registered by the patients on a special form. Vasomotor symptoms, such as sweats and hot flushes, were recorded 3 days prior to each examination. In addition, the patients were asked to omit the progestogen treatment in ‘cycle’ number 7 and to register the symptoms during days 5-7 in this tablet-free week. The number of sweats on corresponding days in treatment ‘cycle’ number 6 and 7 were then compared i.e. with and without the MPA complement. All patients completed 6 mth of treatment but thereafter 3 women left the study because they experienced the curettage as painful, but continued treatment and conventional control visits. Nine patients withdrew after 12-30 mth of treatment. Five of them dropped out because they did not want to use sex hormones any longer because of fear of side effects, 2 stopped because of painful bleedings while nausea and depression were the withdrawal reasons for the other 2 women. The observation period included 1026 treatment months. Statistics Conventional methods were used for calculation of mean, standard deviation and standard error of the mean. For calculation of statistical significance Student’s t-test for paired samples was used.
Results A significant decrease in the serum concentration of FSH from 11.1 + 0.7 pg/l (mean f SEM) to 5.7 + 0.4 pg/l (P < 0.001) was noted after 6 mth of treatment compared to pretreatment values. No significant changes during treatment occurred in blood pressure and body weight (see Table I). Vasomotor symptoms A rapid decrease of the number of sweats and hot flushes was found and no vasomotor symptoms were present after 6 and 36 mth of treatment. The average TABLE
I
MEAN VALUES (*SEM) OF BLOOD PRESSURE WOMEN TREATED WITH A COMBINATION MEDROXYPROGESTERONE ACETATE DURING
AND BODY WEIGHT IN MENOPAUSAL OF CONJUGATED OESTROGENS AND 3 YR.
Before treatment (n = 34)
6 mth of treatment (n=34)
36 mth of treatment (n = 22)
136 84
138 84
141 86
Blood pressure (mm Hg) systolic diastolic Body weight (kg)
+4.8 k1.8
67.0 + 0.9
i5.1 Al.2
66.3 f 1.2
+5.2 +1.9
66.8k1.2
58
number of sweats per day per patient was reduced from 4.5 to zero and the corresponding decrease for hot flushes was 6.2 to zero. Twenty-eight patients recorded a comparison of vasomotor symptoms during the oestrogen-free period in treatment ‘cycles’ 6 and 7. Fifteen women reported a return of sweats and hot flushes in ‘cycle’ 7 when they excluded the MPA tablet while the remainder did not experience any symptoms. Bleeding patterns (Fig. 1)
In 10 cases there were no bleedings at all. During the first 6 mth, 16 of the patients registered a withdrawal bleeding beginning on the 1st to 4th day of the oestrogen treatment period. In 10 of these cases the bleeding was noted as a bloody discharge for 2 or 3 days. In 6 of the women bleeding, described as spotting, began during the 1st to 3rd day of the MPA treatment. Two women reported a small bleeding both at the start of the oestrogen and MPA periods for 6 mth, but this pattern changed and later spottings appeared only when changing to oestrogen treatment. Because of a vaginal bleeding in the middle of respectively the first and second treatment ‘cycle’ in 2 women, endometrial curettages were performed and the histopathological findings showed irregular proliferation without atypia. During treatment the incidence of bleeding episodes decreased gradually (Fig. 1). After 36 mth of treatment 15 of the remaining 22 women had no bleeding at all. Two had bleedings during the MPA period and 5 women had sparse bleedings at the start of the oestrogen treatment. Morphology
Endometrial biopsies were taken after 6 mth of treatment from all but 1 patient who had a cervical stenosis. Biopsies were obtained from all patients left in the study
C]OESTR~OEN
?? MPA
TREATMENT
PERIOD
PERIOD
CYCLES
Fig. 1. The mean number of days with bleeding per patient in a group of post-menopausal women treated with conjugated equine oestrogens and medroxyprogesterone acetate during treatment months l-6 (n = 34) and during month 36 (n = 22)
II
sample
* Endometrial
of surface
1
34 22
6
30-36
mainly consisting
No sample obtained
Mohths of treatment
Number of women
epithelium
3 1
Sample * not representative
Endometrial
to evaluate.
12 11
17 6 and not possible
Mainly weak secretion
Mainly inactive
character
1 2
Mainly proliferation
ENDOMETRIAL HISTOPATHOLOGY IN POST-MENOPAUSAL WOMEN TREATED WITH CONJUGATED MEDROXYPROGESTERONE ACETATE IN SEQUENTIAL TREATMENT OVER A 3-YR PERIOD.
TABLE
1
Hyperplasia
EQUINE
1
_
Hyperplasia with atypia
OESTROGENS
AND
60
after 3 yr of treatment. The results from the histopathological examination are shown in Table II. The endometrium was thin in most women usually with rather few but irregular glands. Most women showed inactive or weakly secretory epithelium. In cases of secretion early changes with basal vacuoles dominated. However, in 2 cases an irregular proliferative character developed with signs of secretion only in small areas. In 2 other patients endometrial hyperplasia was found after 2.5, and 3 yr, respectively. One of these patients had formerly reacted towards unopposed oestrogen therapy with hyperplasia. A biopsy was repeated almost 6 mth later and the endometrium was then of a more secretory character in spite of the unchanged regimen but still there were slightly hyperplastic areas. In the second woman an atypical hyperplasia was found and a conventional dilatation and curettage (D. & C.) was performed 6 wk after stopping hormone treatment. Histopathology now revealed a mostly inactive endometrium but still small fragments with atypical glands were found. Therefore, this woman was treated for 6 wk with 10 mg medroxyprogesterone acetate daily without oestrogen supplement before another D. & C. was performed. The endometrium was then atrophic and inactive. In a subsample of 8 patients biopsies were obtained after 3 wk of conjugated oestrogen therapy in the first treatment cycle. All patients had a proliferative endometrium and in 1 case slight signs of hyperplasia were found. After 6 months of treatment weak secretion or inactivity of the endometrium was found in all these patients. The endometrium from the woman with hyperstimulation is shown in Fig. 2.
Fig. 2A. Endometrial biopsy after 3 wk of conjugated equine oestrogens (1.25 mg/day). Irregular glands with proliferative epithelium, in places with hyperplastic tendency and pseudostratification. Several mitoses in glands and stroma. (Van Gieson, x 20)
61
Fig. 2B. Same case, biopsy taken in the 6th treatment cycle after 5 days of 5 mg medroxyprogesterone acetate daily. Inactivity with few small glands and with low epithelium. (Van Gieson. x 200)
Side effects
Four women complained of dysmenorrhoea during period. Three women experienced breast tenderness migraine-like headache during the MPA period.
1 to 3 days of the bleeding and 2 women reported a
Discussion Several reports have implicated exogenous oestrogens as a possible cause of endometrial cancer in post-menopausal women [1,2,12]. The frequency of hyperplasia after a high dose of unopposed oestrogen therapy in post-menopausal women has been reported by different investigators to vary from 15 to 33% [3,13]. A reduction of the incidence of hyperplasia to about 1.2% was found with the addition of progestogen treatment for 7-10 days while the incidence was reduced to zero with more than 10 days progestogen exposure each month [3]. It has also been emphasized that the duration of treatment rather than the dose of progestogen given was important in inducing this protective effect. Experimental studies on the endometrium report a suppression of DNA synthesis and increased production of oestradiol 17P-dehydrogenase by lower dosages of progestogens than those commonly used in clinical practice today. No clear dose-response relationship was apparent with four different doses of norethisterone [5]. In the present study a dose of 5 mg MPA was chosen since in a previous pilot study (unpubl. data) we found similar effects on the endometrium due to 2.5-10 mg
62
of MPA during 7-14 days, as judged from histopathological studies. All women responded with a uniform weak secretory transformation of the endometrium. In this study the MPA tablets were given to the patients without interruption in sequence after 21 days of treatment with CE. When two medication-free days between the oestrogen and the MPA periods were inserted, a reduction of the number of days with bleeding was obtained. The progestogen could thus exert an ‘unopposed’ activity on the endometrium for 5 days as the serum concentrations of oestrogens in most patients reach baseline levels within 48 hr [14,15]. Bleeding patterns during treatment were acceptable for the patients as they were regular and sparse. Bleedings occurred during the 1st to the 4th day of the MPA or oestrogen periods. Many women had previously had rather abundant withdrawal bleedings on oestrogen-progestogen regimens and for them the reduction of ‘menstrual flow’ was a positive experience. Withdrawal bleedings were gradually reduced and during the last year about 30% of the patients registered spottings mostly appearing in the beginning of the oestrogen period. It is known that various parameters react to sex hormones in different ways. This was well illustrated for conjugated equine oestrogens by Geola and coworkers [16]. They found for example that a dose of 1.25 mg of CE given on a daily basis for 6 wk was necessary to change significantly the percentage superficial cells of the vagina while 0.15 mg of CE under the same conditions induced an increase of serum sex hormone binding globulin. Also well established is the fact that different women need different doses for amelioration of symptoms. In the present study a relative large dose (1.25 mg/day) of CE was used as replacement therapy. According to our present experience half of that dose is enough to suppress vasomotor symptoms for most post-menopausal women. The effect on vasomotor symptoms was good in all women and treatment was well tolerated. When comparing the number of sweats during the oestrogen-free period in treatment ‘cycles’ number 6 and 7 a higher frequency of symptoms were found in most women when MP was not given. This observation confirms previous reports of a positive effect of medroxyprogesterone acetate on vasomotor complaints [7,8]. Two patients in the present study showed irregular endometrial hyperplasia, one with atypia, after 2.5 and 3 yr of treatment respectively. One of these women (the one without atypia) had a slight unscheduled bleeding i.e. it did not appear in the MPA period or during the first days of the oestrogen period. In spite of unchanged therapy the endometrial sample taken 6 mth later in this case was less hyperplastic and more secretory. However, the observation of hyperplasia in 2 women emphasizes the importance of studying endometrial effects when sex steroids are administered for long periods. Progestogens have been advocated in reversing various degree of hyperplasia to normal endometrial epithelium [4,17] and the beneficial effect of such a treatment was illustrated in the patient with atypical hyperplasia. In a subgroup sampled after 3 wk of treatment with 1.25 mg CE daily in the first ‘treatment cycle’ all women had a proliferative endometrium, in one case with a slightly hyperplastic character. After 6 months of treatment no signs of hyperplasia could be found (Fig. 2). However, large individual variations in the endometrial response to hormone therapy, either oestrogenic or combined are usually found as was likewise illustrated
63
in this material. It may therefore be wise to perform an endometrial biopsy routinely after 2-3 yr of treatment even if a progestogen is added. Apparently the regimen of conjugated oestrogens and MPA tested in the present long-term trial did not prevent development of endometrial hyperplasia in all patients. Therefore, in addition to a reduction of the oestrogen dose the MPA period should be prolonged in line with proposals from previous studies [3] in order to avoid this negative ‘side effect’. However, further trials are needed to evaluate the protective effect on the endometrium by such a change of the regimen. References
9 10
11
12 13
14
15
16
17
Hulka BS. Effect of exogenous estrogen on postmenopausal women: The epidemiologic evidence. Obstet Gynecol Surv 1980; 35: 389-399. Weiss NS, Szekely DR, English DR, Schweid AI. Endometrial cancer in relation to patterns of menopausal estrogen use. J Am Med Assoc 1979; 242: 261-264. Paterson MEL, Wade-Evans 1. Sturdee DW. Thorn MH, Studd JWW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. Br Med J 1980; 280: 822-824. Gambrel1 Jr, RD. Massey FM, Castaneda TA, Ugenas AJ. Ricci CA, Wright JM. Use of the progestogen challenge test to reduce the risk of endometrial cancer. Obstet Gynecol 1980: 55: 732-738. Siddle NC, Townsend PT. Young 0, Minardi J, King RIB, Whitehead Ml. Dose-dependent effects of synthetic progestins on the biochemistry of the estrogenized postmenopausal endometrium. Acta Obstet Gynecol Stand 1982; Suppl 106: 17-22. Borglin NE, Staland B. Oral treatment of menopausal symptoms with natural oestrogens. Acta Obstet Gynecol Stand 1975; Suppl 42: l-11. Bullock JL, Massey MF, Gambrel1 RD. Use of medroxyprogesterone acetate to prevent menopausal symptoms. Obstet Gynecol 1975; 46: 1655168. Schiff I, Tulchinsky D, Cramer D, Ryan J. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. J Am Med Assoc 1980; 244: 1443-1445. Silfverstolpe G, Gustafson A, Samsioe G, Svanborg A. Lipid metabolic studies in oophorectomized women. Effects of three different progestogens. Acta Obstet Gynecol 1979; Suppl 88: 89-95. Crona N, Enk L, Samsioe G, Silfverstolpe G. Skryten A. High-dose depot-medroxyprogesterone acetate (DMPA) - effects on lipid and lipoprotein metabolism. Eur J Obstet Gynecol Reprod Biol 1983; 16: 97-105. Burr IM, Grant DB. Sizonenko PC, Kaplan SL, Grumbach MM. Some critical factors in double antibody radioprecipitating sera for measurement of human LH. FSH and HGH. J Clin Endocrinol Metab 1969; 29: 948-956. Smith DC, Prentice R, Thompson DJ. Herrman WL. Association of exogenous estrogens and endometrial carcinoma. N Engl J Med 1975; 293: 1164-1167. Campbell S, Minardi J, McQueen J, Whitehead MI. The modifying effect of progestogen on the response of the postmenopausal endometrium to exogenous estrogens. Postgrad Med J 1978: 54 Suppl 2: 59-64. and gonadotrophins in postEnglund DE, Johansson EDB. Plasma levels of estrone, estradiol menopausal women after oral and vaginal administration of conjugated equine estrogens (Premarin). Br J Obstet Gynaecol 1978; 85: 957-964. Mattsson L, Cullberg G, Samsioe G. Influence of esterified estrogens and medroxyprogesterone on lipid metabolism and sex steroids. A study in oophorectomized women. Horm Metabol Res 1982: 14: 602-606. Geola FL, Frumar AM, Tataryn IV, Lu KH, Hershman JM. Eggena P. Sambhi MP, Judd HL. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 1980; 51: 620-625. Kistner RW. Estrogens and endometrial cancer. Obstet Gynecol 1976; 48: 479-482.
MAT 0031
55
I
A new combination of conjugated equine oestrogens and medroxyprogesterone for treatment of climacteric complaints G. Cullberg I, F. Knutsson * and L.-k Mattsson ’ ’Department of Obstetrics and Gynaecology, University of Gijteborg, East Hospital, Giiteborg, Sweden; and ’ Department
of
Pathology, University of Gijteborg, Sahlgren S Hospital, Gijteborg, Sweden
(Received
7 November
1983; accepted
after revision
17 April 1984)
Thirty-four post-menopausal women with climacteric complaints were given conjugated equine oestrogens (1.25 mg/day) for 21 days followed by 2 days without hormones and then 5 mg medroxyprogesteroneacetate daily for 5 days. The present trial was designed to study effects on vasomotor symptoms, bleeding patterns and endometrial histopathology. Vasomotor disturbances were completely relieved. No recurrence of symptoms was recorded in the oestrogen-free week. Withdrawal bleedings were regular and slight, which was a positive experience for those women who had previously been treated with other oestrogen-progestogen regimens. In most patients inactive or weak secretory endometrial epithelium was found during treatment. Two women developed differing degrees of hyperplasia after 2.5, and 3 yr, respectively. This fact emphasizes the necessity of adding progestogens for at least 10 days each month even if the oestrogens and progestogens are administered separately. It may also be wise to perform an endometrial biopsy when sex hormones are administered on a long-term basis. (Key words:
Postmenopause,
Conjugated
oestrogens,
Medroxyprogesteroneacetate,
Endometrium)
After the menopause many women experience complaints of vasomotor origin. Both oestrogens and progestogens have been shown to alleviate such symptoms. However, a number of side effects, including endometrial cancer, has been attributed to unopposed oestrogen therapy [1,2]. In recent years combinations of oestrogens and progestogens have been advocated in order to avoid endometrial hyperplasia. Epidemiological and histological studies have shown that the addition of progestogens for at least 10 days every month will protect against hyperplasia and malignant degeneration of the endometrium [3,4]. It has also been reported from biochemical studies of the endometrium that lower dosages of progestogens than those commonly used today could be effective in suppressing effects on the endometrium induced by oestrogens [5].
Reprint requests to; G&an Cullberg S-416 85 Gateborg, Sweden.
03785122/84/$03.00
M.D.,
Department
0 1984 Elsevier Science Publishers
of Obstetrics
B.V.
and Gynaecology,
East Hospital.
56
Cyclical hormone replacement therapy (HRT) is widely used for the treatment of climacteric complaints, but some women experience a recurrence of symptoms in the tablet-free week [6]. Inevitably most patients treated with progestogens for 10 days or more on a monthly basis will experience a withdrawal bleeding which can be abundant and annoying. In an attempt to minimize the number of withdrawal bleedings a sequence combination of conjugated equine oestrogens (CE) and medroxyprogesteroneacetate (MPA) was evaluated. MPA was chosen as the progestogen supplement because of the reported favourable effect on vasomotor symptoms [7,8] as well as evidence that this progestogen may be more inert than the 19-nortestosterone derivatives where lipid metabolism is concerned [9,10]. The present study was undertaken to evaluate the clinical and morphological effects on a long-term basis of a new sequential oestrogen-progestogen treatment for post-menopausal women.
Material and Methods Patients and hormone replacement
therapy
Thirty-four patients with climacteric complaints, mean age 55 yr (range 47-63) were included in the study. They were all post-menopausal and the mean time after the last menstruation was 3.3 yr (range l-11). Their post-menopausal status was verified by analysis of follicle-stimulating hormone in serum (FSH) assessed by a radioimmunoassay method [ll]. Approval for the study was obtained from the Ethics Committee, Faculty of Medicine, University of Goteborg and all the patients gave their informed consent. Conjugated equine oestrogens, 1.25 mg, were given as a single daily dose for 21 days. After 2 days without hormones a 5 mg medroxyprogesterone acetate tablet was given daily for 5 days and the sequence was then repeated. Treatment was planned to continue for 3 yr. Design of the study Examination of the patients was performed before treatment, 6 and 18 mth after and then 3 yr after the start of treatment, or in between in cases of bleeding disturbances. FSH was analysed before and at the control examination after 6 mth. A general physical examination, including blood pressure and body weight measurements, were performed at each visit. Endometrial biopsies were taken on the last day of the MPA tablet administration after 6 and 36 mth of treatment. They were obtained with Randall’s curette under local anaesthesia (Xylocain, Astra 1% without epinephrine) administered as a paracervical block. In addition, a curettage was performed in 8 patients after 21 days of CE in the first treatment cycle. The biopsies were fixed in neutral formalin, embedded in paraffin and sectioned at several levels. Sections were stained according to Van Gieson. All biopsies were examined by one pathologist (FW
57
Bleeding patterns and side effects were registered by the patients on a special form. Vasomotor symptoms, such as sweats and hot flushes, were recorded 3 days prior to each examination. In addition, the patients were asked to omit the progestogen treatment in ‘cycle’ number 7 and to register the symptoms during days 5-7 in this tablet-free week. The number of sweats on corresponding days in treatment ‘cycle’ number 6 and 7 were then compared i.e. with and without the MPA complement. All patients completed 6 mth of treatment but thereafter 3 women left the study because they experienced the curettage as painful, but continued treatment and conventional control visits. Nine patients withdrew after 12-30 mth of treatment. Five of them dropped out because they did not want to use sex hormones any longer because of fear of side effects, 2 stopped because of painful bleedings while nausea and depression were the withdrawal reasons for the other 2 women. The observation period included 1026 treatment months. Statistics Conventional methods were used for calculation of mean, standard deviation and standard error of the mean. For calculation of statistical significance Student’s t-test for paired samples was used.
Results A significant decrease in the serum concentration of FSH from 11.1 + 0.7 pg/l (mean f SEM) to 5.7 + 0.4 pg/l (P < 0.001) was noted after 6 mth of treatment compared to pretreatment values. No significant changes during treatment occurred in blood pressure and body weight (see Table I). Vasomotor symptoms A rapid decrease of the number of sweats and hot flushes was found and no vasomotor symptoms were present after 6 and 36 mth of treatment. The average TABLE
I
MEAN VALUES (*SEM) OF BLOOD PRESSURE WOMEN TREATED WITH A COMBINATION MEDROXYPROGESTERONE ACETATE DURING
AND BODY WEIGHT IN MENOPAUSAL OF CONJUGATED OESTROGENS AND 3 YR.
Before treatment (n = 34)
6 mth of treatment (n=34)
36 mth of treatment (n = 22)
136 84
138 84
141 86
Blood pressure (mm Hg) systolic diastolic Body weight (kg)
+4.8 k1.8
67.0 + 0.9
i5.1 Al.2
66.3 f 1.2
+5.2 +1.9
66.8k1.2
58
number of sweats per day per patient was reduced from 4.5 to zero and the corresponding decrease for hot flushes was 6.2 to zero. Twenty-eight patients recorded a comparison of vasomotor symptoms during the oestrogen-free period in treatment ‘cycles’ 6 and 7. Fifteen women reported a return of sweats and hot flushes in ‘cycle’ 7 when they excluded the MPA tablet while the remainder did not experience any symptoms. Bleeding patterns (Fig. 1)
In 10 cases there were no bleedings at all. During the first 6 mth, 16 of the patients registered a withdrawal bleeding beginning on the 1st to 4th day of the oestrogen treatment period. In 10 of these cases the bleeding was noted as a bloody discharge for 2 or 3 days. In 6 of the women bleeding, described as spotting, began during the 1st to 3rd day of the MPA treatment. Two women reported a small bleeding both at the start of the oestrogen and MPA periods for 6 mth, but this pattern changed and later spottings appeared only when changing to oestrogen treatment. Because of a vaginal bleeding in the middle of respectively the first and second treatment ‘cycle’ in 2 women, endometrial curettages were performed and the histopathological findings showed irregular proliferation without atypia. During treatment the incidence of bleeding episodes decreased gradually (Fig. 1). After 36 mth of treatment 15 of the remaining 22 women had no bleeding at all. Two had bleedings during the MPA period and 5 women had sparse bleedings at the start of the oestrogen treatment. Morphology
Endometrial biopsies were taken after 6 mth of treatment from all but 1 patient who had a cervical stenosis. Biopsies were obtained from all patients left in the study
C]OESTR~OEN
?? MPA
TREATMENT
PERIOD
PERIOD
CYCLES
Fig. 1. The mean number of days with bleeding per patient in a group of post-menopausal women treated with conjugated equine oestrogens and medroxyprogesterone acetate during treatment months l-6 (n = 34) and during month 36 (n = 22)
II
sample
* Endometrial
of surface
1
34 22
6
30-36
mainly consisting
No sample obtained
Mohths of treatment
Number of women
epithelium
3 1
Sample * not representative
Endometrial
to evaluate.
12 11
17 6 and not possible
Mainly weak secretion
Mainly inactive
character
1 2
Mainly proliferation
ENDOMETRIAL HISTOPATHOLOGY IN POST-MENOPAUSAL WOMEN TREATED WITH CONJUGATED MEDROXYPROGESTERONE ACETATE IN SEQUENTIAL TREATMENT OVER A 3-YR PERIOD.
TABLE
1
Hyperplasia
EQUINE
1
_
Hyperplasia with atypia
OESTROGENS
AND
60
after 3 yr of treatment. The results from the histopathological examination are shown in Table II. The endometrium was thin in most women usually with rather few but irregular glands. Most women showed inactive or weakly secretory epithelium. In cases of secretion early changes with basal vacuoles dominated. However, in 2 cases an irregular proliferative character developed with signs of secretion only in small areas. In 2 other patients endometrial hyperplasia was found after 2.5, and 3 yr, respectively. One of these patients had formerly reacted towards unopposed oestrogen therapy with hyperplasia. A biopsy was repeated almost 6 mth later and the endometrium was then of a more secretory character in spite of the unchanged regimen but still there were slightly hyperplastic areas. In the second woman an atypical hyperplasia was found and a conventional dilatation and curettage (D. & C.) was performed 6 wk after stopping hormone treatment. Histopathology now revealed a mostly inactive endometrium but still small fragments with atypical glands were found. Therefore, this woman was treated for 6 wk with 10 mg medroxyprogesterone acetate daily without oestrogen supplement before another D. & C. was performed. The endometrium was then atrophic and inactive. In a subsample of 8 patients biopsies were obtained after 3 wk of conjugated oestrogen therapy in the first treatment cycle. All patients had a proliferative endometrium and in 1 case slight signs of hyperplasia were found. After 6 months of treatment weak secretion or inactivity of the endometrium was found in all these patients. The endometrium from the woman with hyperstimulation is shown in Fig. 2.
Fig. 2A. Endometrial biopsy after 3 wk of conjugated equine oestrogens (1.25 mg/day). Irregular glands with proliferative epithelium, in places with hyperplastic tendency and pseudostratification. Several mitoses in glands and stroma. (Van Gieson, x 20)
61
Fig. 2B. Same case, biopsy taken in the 6th treatment cycle after 5 days of 5 mg medroxyprogesterone acetate daily. Inactivity with few small glands and with low epithelium. (Van Gieson. x 200)
Side effects
Four women complained of dysmenorrhoea during period. Three women experienced breast tenderness migraine-like headache during the MPA period.
1 to 3 days of the bleeding and 2 women reported a
Discussion Several reports have implicated exogenous oestrogens as a possible cause of endometrial cancer in post-menopausal women [1,2,12]. The frequency of hyperplasia after a high dose of unopposed oestrogen therapy in post-menopausal women has been reported by different investigators to vary from 15 to 33% [3,13]. A reduction of the incidence of hyperplasia to about 1.2% was found with the addition of progestogen treatment for 7-10 days while the incidence was reduced to zero with more than 10 days progestogen exposure each month [3]. It has also been emphasized that the duration of treatment rather than the dose of progestogen given was important in inducing this protective effect. Experimental studies on the endometrium report a suppression of DNA synthesis and increased production of oestradiol 17P-dehydrogenase by lower dosages of progestogens than those commonly used in clinical practice today. No clear dose-response relationship was apparent with four different doses of norethisterone [5]. In the present study a dose of 5 mg MPA was chosen since in a previous pilot study (unpubl. data) we found similar effects on the endometrium due to 2.5-10 mg
62
of MPA during 7-14 days, as judged from histopathological studies. All women responded with a uniform weak secretory transformation of the endometrium. In this study the MPA tablets were given to the patients without interruption in sequence after 21 days of treatment with CE. When two medication-free days between the oestrogen and the MPA periods were inserted, a reduction of the number of days with bleeding was obtained. The progestogen could thus exert an ‘unopposed’ activity on the endometrium for 5 days as the serum concentrations of oestrogens in most patients reach baseline levels within 48 hr [14,15]. Bleeding patterns during treatment were acceptable for the patients as they were regular and sparse. Bleedings occurred during the 1st to the 4th day of the MPA or oestrogen periods. Many women had previously had rather abundant withdrawal bleedings on oestrogen-progestogen regimens and for them the reduction of ‘menstrual flow’ was a positive experience. Withdrawal bleedings were gradually reduced and during the last year about 30% of the patients registered spottings mostly appearing in the beginning of the oestrogen period. It is known that various parameters react to sex hormones in different ways. This was well illustrated for conjugated equine oestrogens by Geola and coworkers [16]. They found for example that a dose of 1.25 mg of CE given on a daily basis for 6 wk was necessary to change significantly the percentage superficial cells of the vagina while 0.15 mg of CE under the same conditions induced an increase of serum sex hormone binding globulin. Also well established is the fact that different women need different doses for amelioration of symptoms. In the present study a relative large dose (1.25 mg/day) of CE was used as replacement therapy. According to our present experience half of that dose is enough to suppress vasomotor symptoms for most post-menopausal women. The effect on vasomotor symptoms was good in all women and treatment was well tolerated. When comparing the number of sweats during the oestrogen-free period in treatment ‘cycles’ number 6 and 7 a higher frequency of symptoms were found in most women when MP was not given. This observation confirms previous reports of a positive effect of medroxyprogesterone acetate on vasomotor complaints [7,8]. Two patients in the present study showed irregular endometrial hyperplasia, one with atypia, after 2.5 and 3 yr of treatment respectively. One of these women (the one without atypia) had a slight unscheduled bleeding i.e. it did not appear in the MPA period or during the first days of the oestrogen period. In spite of unchanged therapy the endometrial sample taken 6 mth later in this case was less hyperplastic and more secretory. However, the observation of hyperplasia in 2 women emphasizes the importance of studying endometrial effects when sex steroids are administered for long periods. Progestogens have been advocated in reversing various degree of hyperplasia to normal endometrial epithelium [4,17] and the beneficial effect of such a treatment was illustrated in the patient with atypical hyperplasia. In a subgroup sampled after 3 wk of treatment with 1.25 mg CE daily in the first ‘treatment cycle’ all women had a proliferative endometrium, in one case with a slightly hyperplastic character. After 6 months of treatment no signs of hyperplasia could be found (Fig. 2). However, large individual variations in the endometrial response to hormone therapy, either oestrogenic or combined are usually found as was likewise illustrated
63
in this material. It may therefore be wise to perform an endometrial biopsy routinely after 2-3 yr of treatment even if a progestogen is added. Apparently the regimen of conjugated oestrogens and MPA tested in the present long-term trial did not prevent development of endometrial hyperplasia in all patients. Therefore, in addition to a reduction of the oestrogen dose the MPA period should be prolonged in line with proposals from previous studies [3] in order to avoid this negative ‘side effect’. However, further trials are needed to evaluate the protective effect on the endometrium by such a change of the regimen. References
9 10
11
12 13
14
15
16
17
Hulka BS. Effect of exogenous estrogen on postmenopausal women: The epidemiologic evidence. Obstet Gynecol Surv 1980; 35: 389-399. Weiss NS, Szekely DR, English DR, Schweid AI. Endometrial cancer in relation to patterns of menopausal estrogen use. J Am Med Assoc 1979; 242: 261-264. Paterson MEL, Wade-Evans 1. Sturdee DW. Thorn MH, Studd JWW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. Br Med J 1980; 280: 822-824. Gambrel1 Jr, RD. Massey FM, Castaneda TA, Ugenas AJ. Ricci CA, Wright JM. Use of the progestogen challenge test to reduce the risk of endometrial cancer. Obstet Gynecol 1980: 55: 732-738. Siddle NC, Townsend PT. Young 0, Minardi J, King RIB, Whitehead Ml. Dose-dependent effects of synthetic progestins on the biochemistry of the estrogenized postmenopausal endometrium. Acta Obstet Gynecol Stand 1982; Suppl 106: 17-22. Borglin NE, Staland B. Oral treatment of menopausal symptoms with natural oestrogens. Acta Obstet Gynecol Stand 1975; Suppl 42: l-11. Bullock JL, Massey MF, Gambrel1 RD. Use of medroxyprogesterone acetate to prevent menopausal symptoms. Obstet Gynecol 1975; 46: 1655168. Schiff I, Tulchinsky D, Cramer D, Ryan J. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. J Am Med Assoc 1980; 244: 1443-1445. Silfverstolpe G, Gustafson A, Samsioe G, Svanborg A. Lipid metabolic studies in oophorectomized women. Effects of three different progestogens. Acta Obstet Gynecol 1979; Suppl 88: 89-95. Crona N, Enk L, Samsioe G, Silfverstolpe G. Skryten A. High-dose depot-medroxyprogesterone acetate (DMPA) - effects on lipid and lipoprotein metabolism. Eur J Obstet Gynecol Reprod Biol 1983; 16: 97-105. Burr IM, Grant DB. Sizonenko PC, Kaplan SL, Grumbach MM. Some critical factors in double antibody radioprecipitating sera for measurement of human LH. FSH and HGH. J Clin Endocrinol Metab 1969; 29: 948-956. Smith DC, Prentice R, Thompson DJ. Herrman WL. Association of exogenous estrogens and endometrial carcinoma. N Engl J Med 1975; 293: 1164-1167. Campbell S, Minardi J, McQueen J, Whitehead MI. The modifying effect of progestogen on the response of the postmenopausal endometrium to exogenous estrogens. Postgrad Med J 1978: 54 Suppl 2: 59-64. and gonadotrophins in postEnglund DE, Johansson EDB. Plasma levels of estrone, estradiol menopausal women after oral and vaginal administration of conjugated equine estrogens (Premarin). Br J Obstet Gynaecol 1978; 85: 957-964. Mattsson L, Cullberg G, Samsioe G. Influence of esterified estrogens and medroxyprogesterone on lipid metabolism and sex steroids. A study in oophorectomized women. Horm Metabol Res 1982: 14: 602-606. Geola FL, Frumar AM, Tataryn IV, Lu KH, Hershman JM. Eggena P. Sambhi MP, Judd HL. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 1980; 51: 620-625. Kistner RW. Estrogens and endometrial cancer. Obstet Gynecol 1976; 48: 479-482.