Maturitas, 14 (1991) 43-48 Elsevier Scientific Publishers Ireland Ltd.
43
MAT 00642
Effects of oestradiol valerate plus two different progestogens on serum lipids during post-menopausal replacement therapy M. Makkonen”, Departments
S. Saarikoski”
of UObstetrics and Gynaecology
and I. Penttilib
and hClinical Chemistry. Kuopio University Hospital, Kuopio (Finland)
(Received October 8. 1990: revision received March 12, 1991; accepted March 16, 1991)
A total of 27 post-menopausal women were treated with hormone replacement therapy over a period of 6 months for climacteric symptoms. Serum total cholesterol, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol and triglyceride concentrations were determined before therapy commenced and duringthe third and sixth treatment cycles. One group (13 women) was treated with 2 mg oestradiol valerate plus 7.5 mg megestrol acetate (EV + MA). The other group (14 women)received2 mg EV plus 0.25 mg norgestrel (Cyclabil). The serum total cholesterol concentration decreased in both groups, the fall being more marked in that treated with Cyclabil. The serum LDLcholesterol and triglyceride concentrations also decreased in both groups. The serum HDL-cholesterol concentration fell in the Cyclabil group but did not alter in the women treated with EV + MA. Our results suggest that the cyclic addition of megestrol acetate, a 17-a-hydroxyprogesterone derivative, to oestrogen therapy does not affect the serum HDL-cholesterol concentration. whereas norgestrel, which is a 19-nortestosterone derivative, causes it to decrease.
Key words: oestrogen treatment; oestradiol valerate; progestogen treatment; megestrol acetate; norgestrel; climacteric hormone therapy
Introduction
Hormone therapy for climacteric symptoms is known to be effective. The cyclic administration of progestogens during oestrogen replacement therapy is becoming increasingly widespread as a result of the evidence indicating that it exerts a prophylactic action against endometrial hyperplasia and cancer. Several studies have demonstrated that a high serum level of high-density lipoprotein (HDL) cholesterol has a marked prophylactic effect against ischaemic heart disease [ 1,2]. Oestrogens tend to increase the serum concentration of HDL-cholesterol Correspondence to: Maija Makkonen MD, Department of Obstetrics and Gynaecology, Kuopio University Hospital, SF-70210 Kuopio, Finland.
0378-5122/91/$03.50 0 1991 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
44
and triglycerides and to decrease that of low-density-lipoprotein (LDL) cholesterol, whereas androgens have the opposite effect [3]. Derivatives of 19-nortestosterone possess some androgenic activity, but 17-cr-hydroxyprogesterones, which are regarded as ‘pure’ progestogens, have neither oestrogenic nor androgenic properties [4]. Recent studies indicate that progestogens derived from 1Pnortestosterone have a stronger HDL-depressive effect than 17-a-hydroxyprogesterones [6,7]. The purpose of the present investigation was to study the effects on serum lipids of post-menopausal treatment with a sequential combination of oestradiol valerate (EV) and either megestreol acetate (MA) or norgestrel (NGL). Subjects and Methods Subjects
The study population consisted of 27 post-menopausal women with climacteric symptoms who had not menstruated for at least 6 months. The age range was 46-64 years (mean 53.8 years). The patients were randomly allocated to two groups, Group 1 comprising 13 women and Group 2 the remaining 14. Hormonal treatment Each patient received oestrogen-progestogen treatment for 6 months. Group 1 (EV + MA) received 2 mg/day EV alone for 11 days, followed by 2 mg/day EV plus 7.5 mglday MA for 10 days and finally 0.5 mglday EV alone for 7 days. Group 2 (Cyclabil) received 2 mg/day EV alone for 11 days, followed by 2 mg/day EV plus 0.25 mg/day NGL for 10 days and finally placebo for 7 days. The severity of climacteric symptoms was determined before treatment and at the end of the third and sixth treatment cycles using the Kupperman index [8]. Venous blood samples were drawn after an overnight fast l-2 weeks prior to commencement of hormone therapy. A sample was also drawn on day 21 of the third and sixth treatment cycles. Lipid analyses
Determinations of total serum cholesterol, HDL-cholesterol and LDL-cholesterol were carried out enzymatically by means of the cholesterol oxidase-peroxidase technique. The HDL-cholesterol assay was performed after removal of very-lowdensity lipoprotein (VLDL) and LDL [9]. Total triglycerides were also measured using an enzymatic method (Boehringer Mannheim, Germany) and a Hitachi 705 E analyzer. Statistical
methods
The I-test was used to compare ‘the mean values in the two groups. A value of P c 0.05 was regarded as being statistically significant. Results A total of 27 women entered the study. Two patients who received EV + MA were withdrawn from the trial, one because of dizziness and depression and the other
45 TABLE
1
SERUM TOTAL CHOLESTEROL LEVELS BEFORE AND DURING OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment
No. of patients
group
EV+MA Cyclabil
(nmohl;
mean During
Before treatment
I3 14
“P < 0.01 vs. baseline
TABLE
Total cholesterol
S.E.)
treatment
3rd
6th cycle
6.96 f 0.29” 5.99 zt 0.27b,c
7.06 f 6.26 f
1.53 f 0.29 7.02 zt 0.34 value; bP < 0.001 vs. baseline
f
THE 3rd AND 6th MONTHS ACETATE (EV + MA) AND
0.25” 0.27’
value: 'P < 0.05vs.EV + MA.
II
SERUM HIGH-DENSITY-LIPOPROTEIN (HDL) CHOLESTEROL LEVELS BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EM + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment
No. of patients
group
EV+MA Cyclabil
(nmohl;
Before treatment
13 14
“P < 0.001 vs. baseline
TABLE
HDL-cholesterol
I.85 zt 0.12 1.78 f 0.11
mean During
* S.E.) treatment
3rd
6th cycle
1.84 ztz 0.11 1.40 f O.O7”,b
1.83 f 0.15 1.45 * o.ow
value; bP c 0.05 vs. EV + MA.
111
RATIO OF HDL-CHOLESTEROL/TOTAL CHOLESTEROL CONCENTRATION BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EV + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment group
EV+MA Cyclabil
No. of patients
HDL cholesterol/total Before treatment
13 I4
“P < 0.05 vs. baseline
0.25 + 0.01 0.26 f 0.02 value.
cholesterol During
(mean
f
SE.)
treatment
3rd
6th cycle
0.27 + 0.01 0.24 zt 0.02”
0.26 f 0.24 f
0.02 0.01”
46
TABLE
IV
SERUM LOW-DENSITY-LIPOPROTEIN (LDL) CHOLESTEROL LEVELS BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EV + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment group
No. of patients
LDL cholesterol
(nmohl;
Before treatment
EV+MA Cyclabil
13 I4
“P < 0.001 vs. baseline
5.15 f 4.80 f
mean During
0.22 0.22
f
S.E.)
treatment
3rd
6th cycle
4.70 zt 0.231 4.38 zt 0.23”
4.74 k 0.23” 4.44 zt 0.23’
value.
owing to pruritus. Hypermenorrhoea in one woman and headache in another were the reasons for their dropping out of the Cyclabil group. No significant differences were found as regards median age, weight, or diastolic and systolic blood pressure in the women in the two groups prior to treatment. The beneficial effects of the two regimens in controlling climacteric symptoms as measured by the Kupperman index were similar (P < 0.001). The systolic blood pressure was unaffected by the two treatments, but the diastolic pressure was lower during the sixth month of treatment in both groups (P < 0.05). In Group 1 (EV + MA) diastolic blood pressure fell from a mean value of 95.76 mmHg (SE. 3.84) to 90.07 mmHg (S.E. 2.76) and in Group 2 (Cyclabil) from 88.35 mmHg (SE. 2.52) to 82.14 mmHg (SE. 3.46). The serum total cholesterol concentration decreased during treatment in both groups, but the fall was greater in Group 2 (Cyclabil) (Table I). Table II shows that the HDL-cholesterol concentration decreased in Group 2 (Cyclabil) during treatment, but not in Group 1 (EV + MA). The HDLcholesterol/total cholesterol ratio fell in Group 2 (Cyclabil), but was unchanged in Group 1 (EV + MA) (Table III).
TABLE
V
SERUM LEVELS OF TRIGLYCERIDES BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EV + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment group
EV+MA Cyclabil
No. of patients
Triglycerides Before treatment 1.42 zt 0.14 1.37 ?? 0.14
I3 I4
‘P < 0.0001 vs. baseline
value.
(nmohl;
mean
f
During
S.E.) treatment
3rd
6th cycle
I.12 * 0.12” 0.85 zt 0.12”
1.33 ?? 0.11 I.01 f 0.11”
47
Serum LDL-cholesterol concentrations (Table IV) decreased significantly in both treatment groups. Serum triglyceride concentrations had decreased equally in both treatment groups by the third month of treatment, but did not fall thereafter (Table V).
Sequential administration of oestrogens and progestogens is commonly used in the treatment of climacteric symptoms instead of continuous oestrogen therapy. Oestrogen replacement therapy affects lipid metabolism by reducing LDLcholesterol and increasing HDL-cholesterol concentrations [IO-121. This is a favourable effect from the standpoint of coronary disease prevention [2,14] so the lowered levels of LDL-cholesterol shown in our study are advantageous in this respect. A cyclic progestogen is usually added to the treatment regimen to offset the risk of endometrial carcinoma associated with unopposed oestrogen treatment. Progestogens derived from the 1Pnortestosterone series decrease the concentration of serum total cholesterol [ 15- 181 but unfortunately have the same effect on HDLcholesterol [5,7,15,17,18]. Indeed, many previous studies have shown that serum triglycerides are decreased as well [ 15- 17,19,20]. These changes were also seen in the group receiving NGL (Cyclabil) in the present study. On the other hapd, the action of megestrol acetate, a derivative of 17-ohydroxyprogesterone, was found to differ in that it had no effect on the serum HDLcholesterol concentration. Previous studies [5-71 have shown that the addition of medroxyprogesterone (another derivative of 17-a-hydroxyprogesterone) to oestrogen replacement therapy has a similar absence of effect in this respect. The same is also true of natural progesterone, which is used in pre-menopausal bleeding disorders [21]. However, fewer investigations have been carried out using MA. In the study conducted by Ylostalo et al. [ 181the serum HDL-cholesterol concentration decreased in climacteric women treated with sodium oestrone sulphate (1.5 mg/day) and MA (5 mg/day), this observation being at variance with our findings. However, the MA dose was lower than that used in our study (7.5 mg), which may be the reason for the divergent results, another possible explanation being that different oestrogens were used in the studies. Moreover, the serum HDL-concentration results might have been different if the two progestogens had been used in equipotent doses. Since ischaemic heart disease is related to menopause and increasing age, and hormone therapy is being used increasingly widely in climacteric women, attention clearly needs to be paid to the lipid effects of combined oestrogen-progestogen therapy. Our study findings suggest that megestrol acetate offers some advantages over norgestrel in this regard.
I
Kannel WB, Castelli WP, Gordon Intern Med 1979; 90: 85-91.
T. Cholesterol
in the prediction
of atherosclerotic
disease.
Ann
2
Miller NE, Forde OH. Thelle Ds. Mjos OD. The Tromso heart study. High-density lipoprotein coronary heart disease: A prospective case-control study. Lancet 1979; i: 965-968.
and
48 3
Wahl PW, Walden CE, Knopp RH. Warnick CR, Hoover JJ, Hazzard WR. Albers JJ. Lipid and lipoprotein triglyceride and cholesterol interrelationships: Effects of sex, hormone use. and hyperlipidemia. Metabolism 1984: 33: 502-508. Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens- a short review. Postgrad Med J 1978: 54: Suppl 2: I l-24. Hirvonen E, Miilkiinen M. Manninen V. Effects of different progestogens on lipoproteins during
8 9
10
postmenopausal replacement therapy. N Engl J Med 1981; 304: 560-562. Sifverstolpe G, Gustafson A, Samsioe G. Svanborg A. Lipid metabolism studies in oophorectomized women. Effects of three different progestogens. Acta Obstet Gynecol Stand 1979; Suppl88: 89-95. Vejtrop M, Christensen MS, Vejtrop L. Larsen JF. Serum lipoprotein changes in climacteric women induced by sequential therapy with natural estrogens and medroxy-progesterone acetate or norgestrel. Acta Obstet Gynecol Stand 1986; 65: 391-395. Kupperman HS, Blatt MGH, Wiesbader H. et al. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrhea1 indices. J Clin Endocrinol 1953: 13: 688-703. Penttill IM, Voutilainen E, Laitinen M. Juutilainen P. Comparison of different analytical and precipitation methods for direct estimation of serum high-density lipoprotein cholesterol. Stand J Clin Lab Invest 1981; 41: 353-360. Wallentin L. Larsson-Coher U. Postmenopausal oestrogen replacement and lipids. Lancet 1977; i: 1358-1359. Wallace RB. Hoover J, Barret-Connor E et al. Altered plasma lipid and lipoprotein levels associated with oral contraceptive and estrogen use. Lancet 1979; ii: I I I. Bush TL, Barret-Connor E. Noncontraceptive estrogen use and cardiovascular disease. Epidemiol Rev 1985; 7: 80-104. Tikkanen M. Nikkill E. Natural estrogen as an effective treatment for Type II hyperlipoproteinemia in postmenopausal women. Lancet 1978; I I: 490-491. Gorden T, Castelli WP, Hjortland MC, Kannel WB, Dawber DR. High density lipoprotein as a pro-
IS I6
I7 I8 I9 20
21
tective factor against coronary heart disease:The Framingham Study. Am J Med 1977: 62: 707-714. Vilska S, Punnonen R, Rauramo L. Long-term post-menopausal hormone therapy and serum HDLC. total cholesterol and triglycerides. Maturitas 1983; 5: 97-104. Paterson ME, Sturdee DW, Moore B, Whitehead TP. The effect of various regimens of hormone therapy on serum cholesterol and triglyceride concentrations in post-menopausal women. Br J Obstet Gynaecol 1980; 87: 552-560. Lagrelius A. Fredricsson B, Hirt M, Weintraub L. Clinical experience with a low-dose combination of estradiol valerate and levonorgestrel. Acta Obstet Gynecol Stand 1986; Suppl 134: 97- 101. Ylbstalo P, Kauppila A, Kivinen S. Tuimala R. Vihko R. Endocrine and metabolic effects of low dose estrogen-progestin treatment in climacteric women. Obstet Gynecol 1983; 62: 682-686. Christensen NC, Davidsen PC. Secher NJ, Pedersen GT. Serum lipids during oestradiolvalerate/norgestrel treatment of menopausal women. Acta Obstet Gynecol Stand 1975: 54: 213-216. Nielsen FH, Honore E, Kristoffersen K. Secher NJ, Pedersen GT. Changes in serum lipids during treatment with norgestrel oestradiol-valerate and cycloprogynon. Acta Obstet Gynecol Stand 1977; 56: 360-370. Saarikoski S, Yliskoski M, Penttila 1. Sequential use of norethisterone and natural progesterone in pre-menopausal bleeding disorders. Maturitas 1990; 12: 89-97.
43
MAT 00642
Effects of oestradiol valerate plus two different progestogens on serum lipids during post-menopausal replacement therapy M. Makkonen”, Departments
S. Saarikoski”
of UObstetrics and Gynaecology
and I. Penttilib
and hClinical Chemistry. Kuopio University Hospital, Kuopio (Finland)
(Received October 8. 1990: revision received March 12, 1991; accepted March 16, 1991)
A total of 27 post-menopausal women were treated with hormone replacement therapy over a period of 6 months for climacteric symptoms. Serum total cholesterol, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol and triglyceride concentrations were determined before therapy commenced and duringthe third and sixth treatment cycles. One group (13 women) was treated with 2 mg oestradiol valerate plus 7.5 mg megestrol acetate (EV + MA). The other group (14 women)received2 mg EV plus 0.25 mg norgestrel (Cyclabil). The serum total cholesterol concentration decreased in both groups, the fall being more marked in that treated with Cyclabil. The serum LDLcholesterol and triglyceride concentrations also decreased in both groups. The serum HDL-cholesterol concentration fell in the Cyclabil group but did not alter in the women treated with EV + MA. Our results suggest that the cyclic addition of megestrol acetate, a 17-a-hydroxyprogesterone derivative, to oestrogen therapy does not affect the serum HDL-cholesterol concentration. whereas norgestrel, which is a 19-nortestosterone derivative, causes it to decrease.
Key words: oestrogen treatment; oestradiol valerate; progestogen treatment; megestrol acetate; norgestrel; climacteric hormone therapy
Introduction
Hormone therapy for climacteric symptoms is known to be effective. The cyclic administration of progestogens during oestrogen replacement therapy is becoming increasingly widespread as a result of the evidence indicating that it exerts a prophylactic action against endometrial hyperplasia and cancer. Several studies have demonstrated that a high serum level of high-density lipoprotein (HDL) cholesterol has a marked prophylactic effect against ischaemic heart disease [ 1,2]. Oestrogens tend to increase the serum concentration of HDL-cholesterol Correspondence to: Maija Makkonen MD, Department of Obstetrics and Gynaecology, Kuopio University Hospital, SF-70210 Kuopio, Finland.
0378-5122/91/$03.50 0 1991 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
44
and triglycerides and to decrease that of low-density-lipoprotein (LDL) cholesterol, whereas androgens have the opposite effect [3]. Derivatives of 19-nortestosterone possess some androgenic activity, but 17-cr-hydroxyprogesterones, which are regarded as ‘pure’ progestogens, have neither oestrogenic nor androgenic properties [4]. Recent studies indicate that progestogens derived from 1Pnortestosterone have a stronger HDL-depressive effect than 17-a-hydroxyprogesterones [6,7]. The purpose of the present investigation was to study the effects on serum lipids of post-menopausal treatment with a sequential combination of oestradiol valerate (EV) and either megestreol acetate (MA) or norgestrel (NGL). Subjects and Methods Subjects
The study population consisted of 27 post-menopausal women with climacteric symptoms who had not menstruated for at least 6 months. The age range was 46-64 years (mean 53.8 years). The patients were randomly allocated to two groups, Group 1 comprising 13 women and Group 2 the remaining 14. Hormonal treatment Each patient received oestrogen-progestogen treatment for 6 months. Group 1 (EV + MA) received 2 mg/day EV alone for 11 days, followed by 2 mg/day EV plus 7.5 mglday MA for 10 days and finally 0.5 mglday EV alone for 7 days. Group 2 (Cyclabil) received 2 mg/day EV alone for 11 days, followed by 2 mg/day EV plus 0.25 mg/day NGL for 10 days and finally placebo for 7 days. The severity of climacteric symptoms was determined before treatment and at the end of the third and sixth treatment cycles using the Kupperman index [8]. Venous blood samples were drawn after an overnight fast l-2 weeks prior to commencement of hormone therapy. A sample was also drawn on day 21 of the third and sixth treatment cycles. Lipid analyses
Determinations of total serum cholesterol, HDL-cholesterol and LDL-cholesterol were carried out enzymatically by means of the cholesterol oxidase-peroxidase technique. The HDL-cholesterol assay was performed after removal of very-lowdensity lipoprotein (VLDL) and LDL [9]. Total triglycerides were also measured using an enzymatic method (Boehringer Mannheim, Germany) and a Hitachi 705 E analyzer. Statistical
methods
The I-test was used to compare ‘the mean values in the two groups. A value of P c 0.05 was regarded as being statistically significant. Results A total of 27 women entered the study. Two patients who received EV + MA were withdrawn from the trial, one because of dizziness and depression and the other
45 TABLE
1
SERUM TOTAL CHOLESTEROL LEVELS BEFORE AND DURING OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment
No. of patients
group
EV+MA Cyclabil
(nmohl;
mean During
Before treatment
I3 14
“P < 0.01 vs. baseline
TABLE
Total cholesterol
S.E.)
treatment
3rd
6th cycle
6.96 f 0.29” 5.99 zt 0.27b,c
7.06 f 6.26 f
1.53 f 0.29 7.02 zt 0.34 value; bP < 0.001 vs. baseline
f
THE 3rd AND 6th MONTHS ACETATE (EV + MA) AND
0.25” 0.27’
value: 'P < 0.05vs.EV + MA.
II
SERUM HIGH-DENSITY-LIPOPROTEIN (HDL) CHOLESTEROL LEVELS BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EM + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment
No. of patients
group
EV+MA Cyclabil
(nmohl;
Before treatment
13 14
“P < 0.001 vs. baseline
TABLE
HDL-cholesterol
I.85 zt 0.12 1.78 f 0.11
mean During
* S.E.) treatment
3rd
6th cycle
1.84 ztz 0.11 1.40 f O.O7”,b
1.83 f 0.15 1.45 * o.ow
value; bP c 0.05 vs. EV + MA.
111
RATIO OF HDL-CHOLESTEROL/TOTAL CHOLESTEROL CONCENTRATION BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EV + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment group
EV+MA Cyclabil
No. of patients
HDL cholesterol/total Before treatment
13 I4
“P < 0.05 vs. baseline
0.25 + 0.01 0.26 f 0.02 value.
cholesterol During
(mean
f
SE.)
treatment
3rd
6th cycle
0.27 + 0.01 0.24 zt 0.02”
0.26 f 0.24 f
0.02 0.01”
46
TABLE
IV
SERUM LOW-DENSITY-LIPOPROTEIN (LDL) CHOLESTEROL LEVELS BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EV + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment group
No. of patients
LDL cholesterol
(nmohl;
Before treatment
EV+MA Cyclabil
13 I4
“P < 0.001 vs. baseline
5.15 f 4.80 f
mean During
0.22 0.22
f
S.E.)
treatment
3rd
6th cycle
4.70 zt 0.231 4.38 zt 0.23”
4.74 k 0.23” 4.44 zt 0.23’
value.
owing to pruritus. Hypermenorrhoea in one woman and headache in another were the reasons for their dropping out of the Cyclabil group. No significant differences were found as regards median age, weight, or diastolic and systolic blood pressure in the women in the two groups prior to treatment. The beneficial effects of the two regimens in controlling climacteric symptoms as measured by the Kupperman index were similar (P < 0.001). The systolic blood pressure was unaffected by the two treatments, but the diastolic pressure was lower during the sixth month of treatment in both groups (P < 0.05). In Group 1 (EV + MA) diastolic blood pressure fell from a mean value of 95.76 mmHg (SE. 3.84) to 90.07 mmHg (S.E. 2.76) and in Group 2 (Cyclabil) from 88.35 mmHg (SE. 2.52) to 82.14 mmHg (SE. 3.46). The serum total cholesterol concentration decreased during treatment in both groups, but the fall was greater in Group 2 (Cyclabil) (Table I). Table II shows that the HDL-cholesterol concentration decreased in Group 2 (Cyclabil) during treatment, but not in Group 1 (EV + MA). The HDLcholesterol/total cholesterol ratio fell in Group 2 (Cyclabil), but was unchanged in Group 1 (EV + MA) (Table III).
TABLE
V
SERUM LEVELS OF TRIGLYCERIDES BEFORE AND DURING THE 3rd AND 6th MONTHS OF THERAPY WITH OESTRADIOL VALERATE PLUS MEGESTROL ACETATE (EV + MA) AND OESTRADIOL VALERATE PLUS NORGESTREL (CYCLABIL) Treatment group
EV+MA Cyclabil
No. of patients
Triglycerides Before treatment 1.42 zt 0.14 1.37 ?? 0.14
I3 I4
‘P < 0.0001 vs. baseline
value.
(nmohl;
mean
f
During
S.E.) treatment
3rd
6th cycle
I.12 * 0.12” 0.85 zt 0.12”
1.33 ?? 0.11 I.01 f 0.11”
47
Serum LDL-cholesterol concentrations (Table IV) decreased significantly in both treatment groups. Serum triglyceride concentrations had decreased equally in both treatment groups by the third month of treatment, but did not fall thereafter (Table V).
Sequential administration of oestrogens and progestogens is commonly used in the treatment of climacteric symptoms instead of continuous oestrogen therapy. Oestrogen replacement therapy affects lipid metabolism by reducing LDLcholesterol and increasing HDL-cholesterol concentrations [IO-121. This is a favourable effect from the standpoint of coronary disease prevention [2,14] so the lowered levels of LDL-cholesterol shown in our study are advantageous in this respect. A cyclic progestogen is usually added to the treatment regimen to offset the risk of endometrial carcinoma associated with unopposed oestrogen treatment. Progestogens derived from the 1Pnortestosterone series decrease the concentration of serum total cholesterol [ 15- 181 but unfortunately have the same effect on HDLcholesterol [5,7,15,17,18]. Indeed, many previous studies have shown that serum triglycerides are decreased as well [ 15- 17,19,20]. These changes were also seen in the group receiving NGL (Cyclabil) in the present study. On the other hapd, the action of megestrol acetate, a derivative of 17-ohydroxyprogesterone, was found to differ in that it had no effect on the serum HDLcholesterol concentration. Previous studies [5-71 have shown that the addition of medroxyprogesterone (another derivative of 17-a-hydroxyprogesterone) to oestrogen replacement therapy has a similar absence of effect in this respect. The same is also true of natural progesterone, which is used in pre-menopausal bleeding disorders [21]. However, fewer investigations have been carried out using MA. In the study conducted by Ylostalo et al. [ 181the serum HDL-cholesterol concentration decreased in climacteric women treated with sodium oestrone sulphate (1.5 mg/day) and MA (5 mg/day), this observation being at variance with our findings. However, the MA dose was lower than that used in our study (7.5 mg), which may be the reason for the divergent results, another possible explanation being that different oestrogens were used in the studies. Moreover, the serum HDL-concentration results might have been different if the two progestogens had been used in equipotent doses. Since ischaemic heart disease is related to menopause and increasing age, and hormone therapy is being used increasingly widely in climacteric women, attention clearly needs to be paid to the lipid effects of combined oestrogen-progestogen therapy. Our study findings suggest that megestrol acetate offers some advantages over norgestrel in this regard.
I
Kannel WB, Castelli WP, Gordon Intern Med 1979; 90: 85-91.
T. Cholesterol
in the prediction
of atherosclerotic
disease.
Ann
2
Miller NE, Forde OH. Thelle Ds. Mjos OD. The Tromso heart study. High-density lipoprotein coronary heart disease: A prospective case-control study. Lancet 1979; i: 965-968.
and
48 3
Wahl PW, Walden CE, Knopp RH. Warnick CR, Hoover JJ, Hazzard WR. Albers JJ. Lipid and lipoprotein triglyceride and cholesterol interrelationships: Effects of sex, hormone use. and hyperlipidemia. Metabolism 1984: 33: 502-508. Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens- a short review. Postgrad Med J 1978: 54: Suppl 2: I l-24. Hirvonen E, Miilkiinen M. Manninen V. Effects of different progestogens on lipoproteins during
8 9
10
postmenopausal replacement therapy. N Engl J Med 1981; 304: 560-562. Sifverstolpe G, Gustafson A, Samsioe G. Svanborg A. Lipid metabolism studies in oophorectomized women. Effects of three different progestogens. Acta Obstet Gynecol Stand 1979; Suppl88: 89-95. Vejtrop M, Christensen MS, Vejtrop L. Larsen JF. Serum lipoprotein changes in climacteric women induced by sequential therapy with natural estrogens and medroxy-progesterone acetate or norgestrel. Acta Obstet Gynecol Stand 1986; 65: 391-395. Kupperman HS, Blatt MGH, Wiesbader H. et al. Comparative clinical evaluation of estrogenic preparations by the menopausal and amenorrhea1 indices. J Clin Endocrinol 1953: 13: 688-703. Penttill IM, Voutilainen E, Laitinen M. Juutilainen P. Comparison of different analytical and precipitation methods for direct estimation of serum high-density lipoprotein cholesterol. Stand J Clin Lab Invest 1981; 41: 353-360. Wallentin L. Larsson-Coher U. Postmenopausal oestrogen replacement and lipids. Lancet 1977; i: 1358-1359. Wallace RB. Hoover J, Barret-Connor E et al. Altered plasma lipid and lipoprotein levels associated with oral contraceptive and estrogen use. Lancet 1979; ii: I I I. Bush TL, Barret-Connor E. Noncontraceptive estrogen use and cardiovascular disease. Epidemiol Rev 1985; 7: 80-104. Tikkanen M. Nikkill E. Natural estrogen as an effective treatment for Type II hyperlipoproteinemia in postmenopausal women. Lancet 1978; I I: 490-491. Gorden T, Castelli WP, Hjortland MC, Kannel WB, Dawber DR. High density lipoprotein as a pro-
IS I6
I7 I8 I9 20
21
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