Marurifas, 13 (1991) 7-16 Elsevier Scientific Publishers Ireland Ltd.
MAT 00610
Progestogens: therapeutic and adverse effects in early post-menopausal women U. Ma&w, Lkparmenr of Clinical
Chemtitry.
B. Riis and C. Christiansen Glostrup Hospiral. DK-2600 Glostrup ( Dmmark I
(Received 5 March 1990; revision received I7 April 1991);accepted 19 April 1990)
Progestogen treatment is associated with a number of subjective symptoms. In the present study. ! +8 healthy poshnempausal women suffering from mild climacteric symptoms were randomly allocated to I2 weeks of treatment with (a) 2 mg oestradiol valerate combined with cyproterone acetate. mcdroxyprogesterone acetate or levonorgestrel: (b) I.5 mg 17&oestradiol combined with desogestrel: or (c) placebo. Climacteric syqtoms. Kupperman index scores and potential adverse progestogen effects were recorded before treatment iuid three times per month during therapy. All the hormone regimens had a rapid effect. reducing the severity of cliicteric sympzms to about 30% of the baseline values (P < 0.001) within one month. Hot flushes were reduced in severity and/or frequency by 76--100% within 3 months (P C 0.001). The regimens which included hydroxyprogesterone derivatives produced a transient increase in breast tenderness. Other recorded potential adverse progestogen effats showed no signiticant changes during the study. We concluded that the addition of progestogens (whether I%nortestosterone or hydroxyprogesterone derivatives) ooes not produce significant side effects during combined hormone replacement therapy. Key words: (Oestrogedprogestogen.
Climacteric symptoms. Adverse effects:
It is well known that post-menopausal oestrogen replacement therapy alleviates
climactericsymptoms ii,2]. However, unopposed oestrogen treatment increases the risk of endometrial cancer [3,4] and since progestogens have been shown to prevent the development of endometrial hyperplasia and cancer [5,6]. combined oestrogetiprogestogen therapy is widely used for post-menopausal complaints. Progstogens are associated with a number of adverse effects, such as breast tenderness and irritabiity [7-91. Depending on their derivation, progestogens have androgenic and/or oestrogenic effects or anti-androgenic zdfor anti-oestrogenic effects [lo]. The only common effect ascribed to all progestogens is the ability to induce the secretory phase in the oestrogen-primed endometrium [l I]. The effect on post-menopausal symptoms per se of different progestogens used ir. Correspondence lo: U. Madew. Glostrup, Denmark.
Department
of Clinical Chemistry.
03%5122?31/SO3.50 0 1991 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
Glostrup
Hospital
DK-7600
8
combination with oestrogens and the adverse effects produced by these progestogens have not been extensively investigated. In the present study, we examined these effects using 19-nortestosterone derivatives (levonorgestrel (LNG) and desogestrel (DG)) and hydroxyprogesterone derivatives (cyproterone acetate (CPA) and medroxyprogesterone acetate (MPA)). Subjects and methods Participants A large group of women (n = 11 375) aged 45-54 years living in the Glostrup hospital area were sent a questionnaire designed to gather information on last menstrual bleeding, past and present diseases and surgery, and past and current use of drugs. Those who had undergone a natural menopause 6-42 months before the study and apparently had no history of any disease or medication known to influence the variables studied (n = 432) were invited to an information meeting at Glostrup Hospital. The meeting was attended by 274 women, of whom 210 gave their informed consent to participate in a medical screening examination which included clinical history, physical and gynaecological examinations with cytological tests, breast palpation, blood and fasting urine sampling, and measurement of blood pressure. Of these 210 women, 148 were confirmed as being free of any previous or current disease known to influence the variables studied or to Contraindicate the medications used in the trial. These 148 women gave their informed consent (Helsinki Declaration II) to participate in the study, which was approved by the Copenhagen County Ethical Committee. Study design TWO consecutive studies (A and B) were conducted in the same population in accordance with similar protocols. The medication used in study A was packed in boxes and randomly numbered by an independent person working outside the clinic. The tablets containing the continuous combination (A,) and the placebo (A,) were identical in appearance, but the tablets taken by group A, looked different. The first woman attending the clinic was allocated blind to the lowest number, and so on, so that the first 75 women entered study A. In the case of study B it was not possible to produce identical tablets. However, the tablets were packed and numbered as in study A and the next 73 women who visited the clinic were randomly allocated to the study B treatment on a single-blind basis. After the initial examinations the women were randomly assigned to 6 treatment groups. Group A, (n = 25) received continuous treatment with a combination of oestrogen and CPA (days l-28, 2 mg oestradiol valerate (E2V) and 1 mg CPA) as can be seen from Fig. 1. Only one woman dropped out, because of irregular bleeding, while the remaining 24 women (96%) completed the study. Group A, (n = 25) received continuous oestrogen combined sequentially with LNG (days l--16,2 mg E,V; days 17-28, 2 mg E,V + 75 pg LNG. Two women dropped out becaue of headaches, and 23 women (92%) completed the study.
CPA E2 Valerate
LEVO Ez Valerate
Placebo
B,
r
MPA E, Valerate
DES0 17p
- E2
Placebo
Fig. I. Treatment
regimens in the six groups of women and times at which symptoms were recorded (x).
A, (n = 25) received placebo. Ail the women compieted the study. Group B, (n = 25) received a sequential combination of oestrogen and MPA (days l-l 1, 2 mg E2V; days 12-21, 2 mg E,V + IO mg MPA; days 22-28. no treatment). Two women in this group dropped out because of headaches or adverse effects of the medication (depression, irregular bleeding)_ Twenty-three women (92%) completed the study. Group B, (n = 25) received a sequential combination of oestrogen and DG (days l-12, 1.5 mg 17fi-oestradiol (EZ); days 13-24, 1.5 mg E, + 150 pg DG; days 25-28, no treatment). One woman dropped out because of illness unrelated to the study and 24 women (96%) completed the study. Group B, (n = 23) received placebo treatment_ Three women dropped out, two for personal reasons and one because of departure abroad. Twenty women (87%) completed the study. The treatment period was 12 weeks. Blood samples were collected and symptoms recorded at baseline and during the following three cycles: in groups A,. A, and A, on days 2-3, ib-17 and 27-28; in group B, on days 10-I I. 20-2 1 and 23-24; and in groups B, and B, on days 11-12, 23-24 and 26-27 (Fig. 1). These times were chosen because they were linked to the addition of progestogen. i.e. during the maximum oestrogen effect, during the maximum progestogen effect. and after progestogen withdrawal (Fig. 1). Group
10
MethOdS Clinical symptoms were recorded by the subjects, who each tilled in a questionnaire covering the 11 symptoms assessed for the purposes of calculating the menopausal index of Kupperman et al. [12), viz. hot flushes (with and without sweating), paraesthesias, insomnia, nervousness, melancholia, vertigo, fatigue, arthralgias!myalgias, headache, palpitations and formication. Each Kupperman index symptom was rated on a scale from 0 to 3, corresponding to no, slight, moderate and severe complaints. To calculate the Kupperman index, the symptoms were weighted as follows: hot flushes (x4), paraesthesias (X 2), insomnia (X 2), nervousness (x2) and all others fxl).The highest potential score was thus Sl.Symptoms reflecting potential adverse progestogen effects were also recorded, namely stomach pain, breast tenderness, bioating, irritability and acne. These were rated on
TABLE I INITIALMEANVALUESAND RANGESIN THE SIXGROUPSOF POST-MENOPAUSAL WOMEN Group
Age (years)
Menopausal
Serum oestradiol* (nmoUl)
Weight (kg)
Height (cm)
age (months)
Kupperman index (score)
0.134 (O.Ols-l.ooo)
65.6 (47.0-84.7)
164 (155-176)
0.107 (0.027-i
66.4 (52.5-84.9)
164 (155-172)
0.092 (0.026-0.550)
64.6 (52.4-84.9)
163 (155-177)
0.056 (0.02CLO.320)
64.5 (50.G95.4)
163 (145-173)
0.084 (0.016-0.700)
66.2 (52.0-106.0)
163 (153-173)
0.064 (0.027-0.660)
65.2 (55.7-87.4)
165 (M-174)
Al Q’ + CPA (II = 24)
51.4 (48-54)
21.4 (9-36)
10.0 (2-29)
E2V+ LNG (II = 23)
51.6 (47-54)
22.0 (9-37)
(O-24)
Placebo (?I = 25)
50.0 (45-53)
17.3 (7-37)
u-21)
E,V + MPA (n = 23)
51.6 (47-54)
23.1 (9-39)
(h27)
E, + DG (n = 24)
50.5 (45-55)
20.7 (94)
(o--13)
Placebo (n = 20)
50.9 (4654)
24.6 (w-39)
t&24)
A2
7.9
.280)
A3
10.0
% 7.7
B2
6.9
B3
6.2
E2V.oestradiolvalerate;CPA, cyproterone acetate; acetate; E,, 178~oestradiol; DG. desogestrel. *Geometric mean.
LNG. levonorgestrel; MPA. medroxyprogesterone
II
a scale from 0 to 3, corresponding to no, slight, moderate and severe complaints. Lastly, vaginal discomfort, a known consequence of oestrogen deficiency, was recorded and similarly rated. The serum concentrations of Ez were measured using antiserum supplied by Milab, Sweden, and tritium-labelled E, supplied by Amersham. UK. Standards were prepared using agents supplied by Merck, Darmstadt. The intra- and interassay variations were 6% and 15”/0, respectively and the sensitivity was 0.015 nmol/l.
Cai&tions and statistical assessment One-way analysis of variance was used to test the differences between the initial values (Table 1) in all cases except the Kupperman scores, which were tested by means of the Kruskal-Waliis’ one-way analysis of variance. Changes in the serum concentrations of oestradiol were calculated by reference to the geometric mean because of a non-normal data distribution. The pretreatment values in the case of the menopausal index and hot flushes alone were taken as lO@?!for each subject and the 9 subsequent measurements were expressed as percentages of this value. The average changes over time were calculated by cumulating all the values obtained after treatment was started. The t-test for paired data was used to test the significance of differences within the groups and the t-test for unpaired data for differences between the groups. Only women who reported breast tenderness were included in the calculations. Wilcoxon’s test for paired data was used to assess changes in breast tenderness over time.
Table I shows the initial clinical data, serum oestradiol levels and Kupperman scores for the six grctups of women, from which it can be seen that the groups were
e---cm * LEVO
& nmol/l
o----
W
WA
a--
DES0
3--
Placebo
0.20 0.10 I
t 0
t 1
2
3
0.00'
1
0
1
2
3
months Fig. L Geometric mean serum oestradiol values (nmoM) during 3 months of treatment with di!Terent wprogestogen combinations.
12
comparable. The Kupperman scores were generally low, the initial mean values ranging from 6 to 10. Figure 2 plots the serum concentrations of 4 during the three treatment cycles (values expressed as geometric means). The continuous regimens yielded significantly higher constant levels than the placebo. With the sequential regimens there were cyclical changes, whereas in the corresponding placebo group b stayed at a constant low level. The initial values were virtually similar. Figure 3 shows the Kupperman scores in the four treatment groups and the corresponding placebo groups. All the oestrogen treatment regimens had a rapid effect, reducing the Kupperman scores to about 30% of initial values (P < 0.001) within 1 month. There were no significant differences between the effects of the different hormone regimens, whereas the differences between the hormone groups and the placebo groups reached significant levels (P < 0.05-0.001). The sequential oestrogen/progestogen regimens produced no signs of changes in the Kupperman scores at the time of maximum progestogen influence. The placebo groups exhibited Kupperman score fluctuations and in group A, there was a significant decrease in the first month of treatment (P < 0.001) which was not seen in group B,. Figure 4 illustrates the changes in hot flushes in percentage terms. All the oestrogen regimens decreased the severity and/or the frequency of hot flushes by 76-100% within 3 months (P < O.OOl),the most marked reductions being seen in
Kuppermgn index 96 of initial score
lOO+--30-
@----
A* AZ
o-
As
6040-
0’
, 0
I
1
I
2
I
3 months
Fig. 3. Mean percentage Kupperman index values during 3 months of treatment with different oestropnlprogestogen combinations.
Kupperman index. hot fh8shes ‘16 of
initialscore lOO80-
*-
A,
-
AZ
r>---
A,
604020o-
I
I
1
-8-m I
lOO80604020O-
I
I
I
0
1
2
I
3 months
Fig,. 4. Mean percentage values for hot flushes during 3 months of treatment with different oestrogenqxogestogen combinations.
the first month. The differences between groups A,, AZ. B, and the corresponding placebo groups were statistically significant (P < 0.05%0.001). The difference between gro~,p B2 and the corresponding placebo group was borderline statistically significant (P = 0.07). Again, there were no significant differences between the various regimens, and the sequential regimens did not produce variations in hot flushes. Placebo therapy resulted in a small, insignificant decrease. Figure 5 gives an overview of changes in breast tenderness. The incidence increased significantly (P C 0.05-0.Ol) in the groups receiving CPA and MPA. although the increase seemed to be transient in the former (group A,). There were no significant changes in the other groups and none were recorded in other potential adverse progestogen effects.
The women participating in this study were selected as being representative of the female population aged 45-54 years living in an average Danish community [ 131. AS a result of the selection procedure, the women had a relatively low score for climacteric symptoms. However. this optimizes the investigation of climacteric symptoms, because the phenomenon of regression towards the mean is eliminated and the well-known placebo effect on climacteric symptoms is minimized [ 141.
14 Breast tendernor point lo-
Point 10-
-
Al
-
A2
-
4
-
BI
-
82
-
82
O0
1
2
2
months
Fig. 5. Overview of breast tenderness severity ratings during 3 months of treatment with different oestrogetiprogestogen combinations.
The Kupperman index is a well-documented method of recording the severity of climacteric symptoms [ 121. It provides an integral assessment of the commonest symptoms and the questionnaire is easy for the patient to handle and to complete accurately after receiving brief instructions. Unopposed oestrogen therapy increases the risk of endometrial cancer [3,4]. It is therefore generally accepted that the oestrogen component should be combined with a progestogen in either a sequential or a continuous regimen. Combined therapy has been shown to reduce significantly or to eliminate the increased risk of endometrial cancer [5,15]. However, the addition of a progestogen gives rise to potential adverse effects. Firstly, some progestogens reverse the beneficial oestrogenic effect on serum lipids and lipoproteins [l&17] and it has been suggested that this may cancel out oestrogen’s positive effect on cardiovascular disease [16,18]. Secondly, other progestogens have been suspected of giving rise to subjective symptoms [7,8]. The action on the lipid metabolism is obviously related to the type and dose of the progestogen used [ 16,171and this could be true of other effects exerted by progestogens. To represent a wide spectrum of progestogens, two derivatives from the 19-nortestosterone group and two from the hydroxyprogesterone group were included in the present study. Several comparative studies have been carried out using progestogens in incomparable doses 116,191,resulting in a great deal of confusion as to which progestogen
is superior. For post-menopausal hormone replacement therapy the main criterion in the selection of the preferred progestogen is its endometrial transformation potency. This is difficult to assess, but studies [10,20] have indicated that 1 mg CPA and 10 mg MPA may be equivalent. While 125 pg LNG has also been considered to be equivalent to these doses, there is in fact evidence that a LNG dose as low as 75 pg is adequate (211. A dose of 150 pg DG was used in the present study because of its demonstrated ability to control bleeding in pre-menopausal women taking oral contraceptives 122). The long-term effect on the post-menopausal endometrium remains to be studied. However, this dose probably affords the same endometrial protection as the other progestogens used. The oestrogen doses used were chosen because l-2 mg Ez has been shown to prevent bone loss in over 90% of post-menopausal women [23]. Furthermore, with other oestrogen/progestogen combinations this dosage range has been shown to reduce the Kupperman score significantly 1231. It was found in the present study that 2 mg E2V ( 1.5 mg Ez) reduced symptom scores to pre-menopausal levels. Sequential oestrogen therapy has been reported to cause withdrawal symptoms [24], but the present study was not designed to clarify this issue. Relief of symptoms was independent of the regimen and the type of progestogen used in the combmations. The four progestogens caused only minor adverse effects during the 3 months of therapy. The tendency towards increased breast tenderness in the groups receiving CPA and MPA may, however. constitute a problem, and this should be taken into consideration when treating women with a predisposition to this symptom. Ackmw We wish to thank Organon A/S and Schering A/S for supplying the oestrogeu’progestogen combinations and placebo.
1 CampbellS, WhiteheadMI. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaccol 2 3 4 5 6
7 8 9
1977; 4: 3147. Jensen J, christiansen C. Dose-response and withdrawal effects oo climacteric symptoms after hormonal mpkement therapy. A placebo-controlled therapeutic trial. Maturitas 1983; 5: 125-133. S&b DC. Prentice R. Thompson DJ. Hemnann WL. Association of exogenous estrogen and endometrial carcinoma. N Rngl J Med 1975; 293: 1164-l 167. Ziel HR, Finlde WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975; 293: 1167-1176_ GambrelJ RD Jr. Prevention of endometrial cancer with progestogens. Maturitas 1986; 8: 159-I 68. Whitebead ML Townsend PT. Pryse-Davies J, Ryder T, Lane G, Siddle N. Ring RJB. Actions of progehs on the morphology and biochemistry of the endometrium of postmenopausal women receiving low&se estrogea therapy. Am J Obstet Gynecol 1982; 142: 791-795. Gambrell RD Jr. Use of progestogen therapy. Am J Obstet Gynecol 1987; 156: 13W-1313. von Sboultz B. Climacteric complaints as influenced by progestogens. Maturitas 1986: 8: 107-I 12. Hm S. EMtrGm T. J-J&t J, von Schoultz B. Lyre& S. Cyclical mood changes as in the pm tension syndrome during sequential estrogen-progestogen post-menopausal replacement tlterapy. Acta Obstet Gynecoi Stand 1985; 64: 393-397.
16 IO II
I2 13 14 15 I6 17
I8
IQ
20
21 22 23
24
Neuman F. The physiological action of progesterone and the pharmacological eBccts of progestogens - A short review. Postgrad Med J 1978; 54: I l-24. Siddle NC, Townsend PT, Young 0, Minardi J, King RJB. Whitehead MI. Dose-dependent effects ofsynthetic progestins on the biochemistry of the estrogenized post- menopausal endometrium. Acta Obstet Gynecol Stand Suppl 1982; 106: 17-22. Kupperman HS, Meyer HGB, Wiesbader H, Filler W. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrhea1 indices. J Clin Endocrinol 1953; 13: 688-703. Riis 83. Prevention of postmenopausal bone loss. Doctoral Thesis. 1989; 17. Schiff 1. The effects of progestins on vasomotor flushes. J Reprod Med 1982; 27: 498-502. Staiand B. Continuous treatment with a combination of estrogen and gestagen - a way of avoiding endometriai stimulation. Acta Gynecoi Stand 1985; 30: 29-35. Hirvonen E, Miiikonen M, Manninen V. Effects of different progestogens on lipoproteins during post-menopausal replacement therapy. N Engl J Med 1981; 304: 560-563. Jensen J, Niias L, Christiansen C. Cyclic changes in serum cholesterol and lipoproteins following ditferent doses of combined post-menopausal hb..none replacement.therapy. Br J Obstet Gynaecol 1986; 93: 613-618. Stampfer MJ, Wiilett WC, Colditz GA, Rosner B. Speizer FE, Hennekens CH. A prospective study of post-menopausal estrogen therapy and coronary heart disease. N Engl J Med 1985; 313: 1044-1049. Fahraeus L, Larsson-Cohn U, Wallentin L. t.-Norgestrel and progesterone have diierent influences on plasma lipoproteins. Eur J Clin Invest 1983; 13: 447-453. Gibbons WE, Moyer DL, Lobo RA, Roy S, Mishell DR. Biochemical and histologic effects of sequential estrogen/progestin therapy on the endometrium of post-menopausal women. Am J Obstet Gynecoi 1986; 154: 456-461. King RJB. Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertii Sterii 1986; 42: iO62-1066. Kopera H, Weijers MJ. Desogestrel, a new progestogen. In: van Keep PA, Kopera H, eds. Oral contraceptives and lipoproteins. International Health Foundation, 1983: 64-84. Christensen MS, Hagen C. Christiansen C. Transbdi I. Dose-response evaluation of cyclic estrogen/gestagen in post-menopausal women: placebo-controlled trial of its gynecologic and metabolic actions. Am J Obstet Gynecol 1982; 144: 873-879. Borghn NE, Staland B. Oral treatment of menopausal symptoms with natural oestrogens. Acta Obstet Gynecol Stand 1975; 43: i-i I.
MAT 00610
Progestogens: therapeutic and adverse effects in early post-menopausal women U. Ma&w, Lkparmenr of Clinical
Chemtitry.
B. Riis and C. Christiansen Glostrup Hospiral. DK-2600 Glostrup ( Dmmark I
(Received 5 March 1990; revision received I7 April 1991);accepted 19 April 1990)
Progestogen treatment is associated with a number of subjective symptoms. In the present study. ! +8 healthy poshnempausal women suffering from mild climacteric symptoms were randomly allocated to I2 weeks of treatment with (a) 2 mg oestradiol valerate combined with cyproterone acetate. mcdroxyprogesterone acetate or levonorgestrel: (b) I.5 mg 17&oestradiol combined with desogestrel: or (c) placebo. Climacteric syqtoms. Kupperman index scores and potential adverse progestogen effects were recorded before treatment iuid three times per month during therapy. All the hormone regimens had a rapid effect. reducing the severity of cliicteric sympzms to about 30% of the baseline values (P < 0.001) within one month. Hot flushes were reduced in severity and/or frequency by 76--100% within 3 months (P C 0.001). The regimens which included hydroxyprogesterone derivatives produced a transient increase in breast tenderness. Other recorded potential adverse progestogen effats showed no signiticant changes during the study. We concluded that the addition of progestogens (whether I%nortestosterone or hydroxyprogesterone derivatives) ooes not produce significant side effects during combined hormone replacement therapy. Key words: (Oestrogedprogestogen.
Climacteric symptoms. Adverse effects:
It is well known that post-menopausal oestrogen replacement therapy alleviates
climactericsymptoms ii,2]. However, unopposed oestrogen treatment increases the risk of endometrial cancer [3,4] and since progestogens have been shown to prevent the development of endometrial hyperplasia and cancer [5,6]. combined oestrogetiprogestogen therapy is widely used for post-menopausal complaints. Progstogens are associated with a number of adverse effects, such as breast tenderness and irritabiity [7-91. Depending on their derivation, progestogens have androgenic and/or oestrogenic effects or anti-androgenic zdfor anti-oestrogenic effects [lo]. The only common effect ascribed to all progestogens is the ability to induce the secretory phase in the oestrogen-primed endometrium [l I]. The effect on post-menopausal symptoms per se of different progestogens used ir. Correspondence lo: U. Madew. Glostrup, Denmark.
Department
of Clinical Chemistry.
03%5122?31/SO3.50 0 1991 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
Glostrup
Hospital
DK-7600
8
combination with oestrogens and the adverse effects produced by these progestogens have not been extensively investigated. In the present study, we examined these effects using 19-nortestosterone derivatives (levonorgestrel (LNG) and desogestrel (DG)) and hydroxyprogesterone derivatives (cyproterone acetate (CPA) and medroxyprogesterone acetate (MPA)). Subjects and methods Participants A large group of women (n = 11 375) aged 45-54 years living in the Glostrup hospital area were sent a questionnaire designed to gather information on last menstrual bleeding, past and present diseases and surgery, and past and current use of drugs. Those who had undergone a natural menopause 6-42 months before the study and apparently had no history of any disease or medication known to influence the variables studied (n = 432) were invited to an information meeting at Glostrup Hospital. The meeting was attended by 274 women, of whom 210 gave their informed consent to participate in a medical screening examination which included clinical history, physical and gynaecological examinations with cytological tests, breast palpation, blood and fasting urine sampling, and measurement of blood pressure. Of these 210 women, 148 were confirmed as being free of any previous or current disease known to influence the variables studied or to Contraindicate the medications used in the trial. These 148 women gave their informed consent (Helsinki Declaration II) to participate in the study, which was approved by the Copenhagen County Ethical Committee. Study design TWO consecutive studies (A and B) were conducted in the same population in accordance with similar protocols. The medication used in study A was packed in boxes and randomly numbered by an independent person working outside the clinic. The tablets containing the continuous combination (A,) and the placebo (A,) were identical in appearance, but the tablets taken by group A, looked different. The first woman attending the clinic was allocated blind to the lowest number, and so on, so that the first 75 women entered study A. In the case of study B it was not possible to produce identical tablets. However, the tablets were packed and numbered as in study A and the next 73 women who visited the clinic were randomly allocated to the study B treatment on a single-blind basis. After the initial examinations the women were randomly assigned to 6 treatment groups. Group A, (n = 25) received continuous treatment with a combination of oestrogen and CPA (days l-28, 2 mg oestradiol valerate (E2V) and 1 mg CPA) as can be seen from Fig. 1. Only one woman dropped out, because of irregular bleeding, while the remaining 24 women (96%) completed the study. Group A, (n = 25) received continuous oestrogen combined sequentially with LNG (days l--16,2 mg E,V; days 17-28, 2 mg E,V + 75 pg LNG. Two women dropped out becaue of headaches, and 23 women (92%) completed the study.
CPA E2 Valerate
LEVO Ez Valerate
Placebo
B,
r
MPA E, Valerate
DES0 17p
- E2
Placebo
Fig. I. Treatment
regimens in the six groups of women and times at which symptoms were recorded (x).
A, (n = 25) received placebo. Ail the women compieted the study. Group B, (n = 25) received a sequential combination of oestrogen and MPA (days l-l 1, 2 mg E2V; days 12-21, 2 mg E,V + IO mg MPA; days 22-28. no treatment). Two women in this group dropped out because of headaches or adverse effects of the medication (depression, irregular bleeding)_ Twenty-three women (92%) completed the study. Group B, (n = 25) received a sequential combination of oestrogen and DG (days l-12, 1.5 mg 17fi-oestradiol (EZ); days 13-24, 1.5 mg E, + 150 pg DG; days 25-28, no treatment). One woman dropped out because of illness unrelated to the study and 24 women (96%) completed the study. Group B, (n = 23) received placebo treatment_ Three women dropped out, two for personal reasons and one because of departure abroad. Twenty women (87%) completed the study. The treatment period was 12 weeks. Blood samples were collected and symptoms recorded at baseline and during the following three cycles: in groups A,. A, and A, on days 2-3, ib-17 and 27-28; in group B, on days 10-I I. 20-2 1 and 23-24; and in groups B, and B, on days 11-12, 23-24 and 26-27 (Fig. 1). These times were chosen because they were linked to the addition of progestogen. i.e. during the maximum oestrogen effect, during the maximum progestogen effect. and after progestogen withdrawal (Fig. 1). Group
10
MethOdS Clinical symptoms were recorded by the subjects, who each tilled in a questionnaire covering the 11 symptoms assessed for the purposes of calculating the menopausal index of Kupperman et al. [12), viz. hot flushes (with and without sweating), paraesthesias, insomnia, nervousness, melancholia, vertigo, fatigue, arthralgias!myalgias, headache, palpitations and formication. Each Kupperman index symptom was rated on a scale from 0 to 3, corresponding to no, slight, moderate and severe complaints. To calculate the Kupperman index, the symptoms were weighted as follows: hot flushes (x4), paraesthesias (X 2), insomnia (X 2), nervousness (x2) and all others fxl).The highest potential score was thus Sl.Symptoms reflecting potential adverse progestogen effects were also recorded, namely stomach pain, breast tenderness, bioating, irritability and acne. These were rated on
TABLE I INITIALMEANVALUESAND RANGESIN THE SIXGROUPSOF POST-MENOPAUSAL WOMEN Group
Age (years)
Menopausal
Serum oestradiol* (nmoUl)
Weight (kg)
Height (cm)
age (months)
Kupperman index (score)
0.134 (O.Ols-l.ooo)
65.6 (47.0-84.7)
164 (155-176)
0.107 (0.027-i
66.4 (52.5-84.9)
164 (155-172)
0.092 (0.026-0.550)
64.6 (52.4-84.9)
163 (155-177)
0.056 (0.02CLO.320)
64.5 (50.G95.4)
163 (145-173)
0.084 (0.016-0.700)
66.2 (52.0-106.0)
163 (153-173)
0.064 (0.027-0.660)
65.2 (55.7-87.4)
165 (M-174)
Al Q’ + CPA (II = 24)
51.4 (48-54)
21.4 (9-36)
10.0 (2-29)
E2V+ LNG (II = 23)
51.6 (47-54)
22.0 (9-37)
(O-24)
Placebo (?I = 25)
50.0 (45-53)
17.3 (7-37)
u-21)
E,V + MPA (n = 23)
51.6 (47-54)
23.1 (9-39)
(h27)
E, + DG (n = 24)
50.5 (45-55)
20.7 (94)
(o--13)
Placebo (n = 20)
50.9 (4654)
24.6 (w-39)
t&24)
A2
7.9
.280)
A3
10.0
% 7.7
B2
6.9
B3
6.2
E2V.oestradiolvalerate;CPA, cyproterone acetate; acetate; E,, 178~oestradiol; DG. desogestrel. *Geometric mean.
LNG. levonorgestrel; MPA. medroxyprogesterone
II
a scale from 0 to 3, corresponding to no, slight, moderate and severe complaints. Lastly, vaginal discomfort, a known consequence of oestrogen deficiency, was recorded and similarly rated. The serum concentrations of Ez were measured using antiserum supplied by Milab, Sweden, and tritium-labelled E, supplied by Amersham. UK. Standards were prepared using agents supplied by Merck, Darmstadt. The intra- and interassay variations were 6% and 15”/0, respectively and the sensitivity was 0.015 nmol/l.
Cai&tions and statistical assessment One-way analysis of variance was used to test the differences between the initial values (Table 1) in all cases except the Kupperman scores, which were tested by means of the Kruskal-Waliis’ one-way analysis of variance. Changes in the serum concentrations of oestradiol were calculated by reference to the geometric mean because of a non-normal data distribution. The pretreatment values in the case of the menopausal index and hot flushes alone were taken as lO@?!for each subject and the 9 subsequent measurements were expressed as percentages of this value. The average changes over time were calculated by cumulating all the values obtained after treatment was started. The t-test for paired data was used to test the significance of differences within the groups and the t-test for unpaired data for differences between the groups. Only women who reported breast tenderness were included in the calculations. Wilcoxon’s test for paired data was used to assess changes in breast tenderness over time.
Table I shows the initial clinical data, serum oestradiol levels and Kupperman scores for the six grctups of women, from which it can be seen that the groups were
e---cm * LEVO
& nmol/l
o----
W
WA
a--
DES0
3--
Placebo
0.20 0.10 I
t 0
t 1
2
3
0.00'
1
0
1
2
3
months Fig. L Geometric mean serum oestradiol values (nmoM) during 3 months of treatment with di!Terent wprogestogen combinations.
12
comparable. The Kupperman scores were generally low, the initial mean values ranging from 6 to 10. Figure 2 plots the serum concentrations of 4 during the three treatment cycles (values expressed as geometric means). The continuous regimens yielded significantly higher constant levels than the placebo. With the sequential regimens there were cyclical changes, whereas in the corresponding placebo group b stayed at a constant low level. The initial values were virtually similar. Figure 3 shows the Kupperman scores in the four treatment groups and the corresponding placebo groups. All the oestrogen treatment regimens had a rapid effect, reducing the Kupperman scores to about 30% of initial values (P < 0.001) within 1 month. There were no significant differences between the effects of the different hormone regimens, whereas the differences between the hormone groups and the placebo groups reached significant levels (P < 0.05-0.001). The sequential oestrogen/progestogen regimens produced no signs of changes in the Kupperman scores at the time of maximum progestogen influence. The placebo groups exhibited Kupperman score fluctuations and in group A, there was a significant decrease in the first month of treatment (P < 0.001) which was not seen in group B,. Figure 4 illustrates the changes in hot flushes in percentage terms. All the oestrogen regimens decreased the severity and/or the frequency of hot flushes by 76-100% within 3 months (P < O.OOl),the most marked reductions being seen in
Kuppermgn index 96 of initial score
lOO+--30-
@----
A* AZ
o-
As
6040-
0’
, 0
I
1
I
2
I
3 months
Fig. 3. Mean percentage Kupperman index values during 3 months of treatment with different oestropnlprogestogen combinations.
Kupperman index. hot fh8shes ‘16 of
initialscore lOO80-
*-
A,
-
AZ
r>---
A,
604020o-
I
I
1
-8-m I
lOO80604020O-
I
I
I
0
1
2
I
3 months
Fig,. 4. Mean percentage values for hot flushes during 3 months of treatment with different oestrogenqxogestogen combinations.
the first month. The differences between groups A,, AZ. B, and the corresponding placebo groups were statistically significant (P < 0.05%0.001). The difference between gro~,p B2 and the corresponding placebo group was borderline statistically significant (P = 0.07). Again, there were no significant differences between the various regimens, and the sequential regimens did not produce variations in hot flushes. Placebo therapy resulted in a small, insignificant decrease. Figure 5 gives an overview of changes in breast tenderness. The incidence increased significantly (P C 0.05-0.Ol) in the groups receiving CPA and MPA. although the increase seemed to be transient in the former (group A,). There were no significant changes in the other groups and none were recorded in other potential adverse progestogen effects.
The women participating in this study were selected as being representative of the female population aged 45-54 years living in an average Danish community [ 131. AS a result of the selection procedure, the women had a relatively low score for climacteric symptoms. However. this optimizes the investigation of climacteric symptoms, because the phenomenon of regression towards the mean is eliminated and the well-known placebo effect on climacteric symptoms is minimized [ 141.
14 Breast tendernor point lo-
Point 10-
-
Al
-
A2
-
4
-
BI
-
82
-
82
O0
1
2
2
months
Fig. 5. Overview of breast tenderness severity ratings during 3 months of treatment with different oestrogetiprogestogen combinations.
The Kupperman index is a well-documented method of recording the severity of climacteric symptoms [ 121. It provides an integral assessment of the commonest symptoms and the questionnaire is easy for the patient to handle and to complete accurately after receiving brief instructions. Unopposed oestrogen therapy increases the risk of endometrial cancer [3,4]. It is therefore generally accepted that the oestrogen component should be combined with a progestogen in either a sequential or a continuous regimen. Combined therapy has been shown to reduce significantly or to eliminate the increased risk of endometrial cancer [5,15]. However, the addition of a progestogen gives rise to potential adverse effects. Firstly, some progestogens reverse the beneficial oestrogenic effect on serum lipids and lipoproteins [l&17] and it has been suggested that this may cancel out oestrogen’s positive effect on cardiovascular disease [16,18]. Secondly, other progestogens have been suspected of giving rise to subjective symptoms [7,8]. The action on the lipid metabolism is obviously related to the type and dose of the progestogen used [ 16,171and this could be true of other effects exerted by progestogens. To represent a wide spectrum of progestogens, two derivatives from the 19-nortestosterone group and two from the hydroxyprogesterone group were included in the present study. Several comparative studies have been carried out using progestogens in incomparable doses 116,191,resulting in a great deal of confusion as to which progestogen
is superior. For post-menopausal hormone replacement therapy the main criterion in the selection of the preferred progestogen is its endometrial transformation potency. This is difficult to assess, but studies [10,20] have indicated that 1 mg CPA and 10 mg MPA may be equivalent. While 125 pg LNG has also been considered to be equivalent to these doses, there is in fact evidence that a LNG dose as low as 75 pg is adequate (211. A dose of 150 pg DG was used in the present study because of its demonstrated ability to control bleeding in pre-menopausal women taking oral contraceptives 122). The long-term effect on the post-menopausal endometrium remains to be studied. However, this dose probably affords the same endometrial protection as the other progestogens used. The oestrogen doses used were chosen because l-2 mg Ez has been shown to prevent bone loss in over 90% of post-menopausal women [23]. Furthermore, with other oestrogen/progestogen combinations this dosage range has been shown to reduce the Kupperman score significantly 1231. It was found in the present study that 2 mg E2V ( 1.5 mg Ez) reduced symptom scores to pre-menopausal levels. Sequential oestrogen therapy has been reported to cause withdrawal symptoms [24], but the present study was not designed to clarify this issue. Relief of symptoms was independent of the regimen and the type of progestogen used in the combmations. The four progestogens caused only minor adverse effects during the 3 months of therapy. The tendency towards increased breast tenderness in the groups receiving CPA and MPA may, however. constitute a problem, and this should be taken into consideration when treating women with a predisposition to this symptom. Ackmw We wish to thank Organon A/S and Schering A/S for supplying the oestrogeu’progestogen combinations and placebo.
1 CampbellS, WhiteheadMI. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaccol 2 3 4 5 6
7 8 9
1977; 4: 3147. Jensen J, christiansen C. Dose-response and withdrawal effects oo climacteric symptoms after hormonal mpkement therapy. A placebo-controlled therapeutic trial. Maturitas 1983; 5: 125-133. S&b DC. Prentice R. Thompson DJ. Hemnann WL. Association of exogenous estrogen and endometrial carcinoma. N Rngl J Med 1975; 293: 1164-l 167. Ziel HR, Finlde WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975; 293: 1167-1176_ GambrelJ RD Jr. Prevention of endometrial cancer with progestogens. Maturitas 1986; 8: 159-I 68. Whitebead ML Townsend PT. Pryse-Davies J, Ryder T, Lane G, Siddle N. Ring RJB. Actions of progehs on the morphology and biochemistry of the endometrium of postmenopausal women receiving low&se estrogea therapy. Am J Obstet Gynecol 1982; 142: 791-795. Gambrell RD Jr. Use of progestogen therapy. Am J Obstet Gynecol 1987; 156: 13W-1313. von Sboultz B. Climacteric complaints as influenced by progestogens. Maturitas 1986: 8: 107-I 12. Hm S. EMtrGm T. J-J&t J, von Schoultz B. Lyre& S. Cyclical mood changes as in the pm tension syndrome during sequential estrogen-progestogen post-menopausal replacement tlterapy. Acta Obstet Gynecoi Stand 1985; 64: 393-397.
16 IO II
I2 13 14 15 I6 17
I8
IQ
20
21 22 23
24
Neuman F. The physiological action of progesterone and the pharmacological eBccts of progestogens - A short review. Postgrad Med J 1978; 54: I l-24. Siddle NC, Townsend PT, Young 0, Minardi J, King RJB. Whitehead MI. Dose-dependent effects ofsynthetic progestins on the biochemistry of the estrogenized post- menopausal endometrium. Acta Obstet Gynecol Stand Suppl 1982; 106: 17-22. Kupperman HS, Meyer HGB, Wiesbader H, Filler W. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrhea1 indices. J Clin Endocrinol 1953; 13: 688-703. Riis 83. Prevention of postmenopausal bone loss. Doctoral Thesis. 1989; 17. Schiff 1. The effects of progestins on vasomotor flushes. J Reprod Med 1982; 27: 498-502. Staiand B. Continuous treatment with a combination of estrogen and gestagen - a way of avoiding endometriai stimulation. Acta Gynecoi Stand 1985; 30: 29-35. Hirvonen E, Miiikonen M, Manninen V. Effects of different progestogens on lipoproteins during post-menopausal replacement therapy. N Engl J Med 1981; 304: 560-563. Jensen J, Niias L, Christiansen C. Cyclic changes in serum cholesterol and lipoproteins following ditferent doses of combined post-menopausal hb..none replacement.therapy. Br J Obstet Gynaecol 1986; 93: 613-618. Stampfer MJ, Wiilett WC, Colditz GA, Rosner B. Speizer FE, Hennekens CH. A prospective study of post-menopausal estrogen therapy and coronary heart disease. N Engl J Med 1985; 313: 1044-1049. Fahraeus L, Larsson-Cohn U, Wallentin L. t.-Norgestrel and progesterone have diierent influences on plasma lipoproteins. Eur J Clin Invest 1983; 13: 447-453. Gibbons WE, Moyer DL, Lobo RA, Roy S, Mishell DR. Biochemical and histologic effects of sequential estrogen/progestin therapy on the endometrium of post-menopausal women. Am J Obstet Gynecoi 1986; 154: 456-461. King RJB. Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertii Sterii 1986; 42: iO62-1066. Kopera H, Weijers MJ. Desogestrel, a new progestogen. In: van Keep PA, Kopera H, eds. Oral contraceptives and lipoproteins. International Health Foundation, 1983: 64-84. Christensen MS, Hagen C. Christiansen C. Transbdi I. Dose-response evaluation of cyclic estrogen/gestagen in post-menopausal women: placebo-controlled trial of its gynecologic and metabolic actions. Am J Obstet Gynecol 1982; 144: 873-879. Borghn NE, Staland B. Oral treatment of menopausal symptoms with natural oestrogens. Acta Obstet Gynecol Stand 1975; 43: i-i I.
