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Effect of oestrogen and progesterone on fasting serum cholesterol and triglyceride levels in post-menopausal women
Int. J. Gynaecol. Obstet., 1982,20:
International
91-97
Federation of Gynaecology & Obstetrics
EFFECT OF OESTROGEN AND PROGESTERONE ON FASTING SERUM CHOLESTEROL AND TRIGLYCERIDE LEVELS IN POST-MENOPAUSAL WOMEN
T.R. VARMA and JOHN MORSMAN St. George’s Hospital, Cranmer Terrace, London SW1 7
ORE, UK
(Received May 21st, 1981) (Accepted July 9th, 1981)
Abstract Varma TR, Morsman J (St. George’s Hospital, Cranmer Terrace, London SW1 7 ORE, UK). Effect of oestrogen and progesterone on fasting serum cholesterol and triglyceride levels in post-menopausal women. Int J Gynaecol Obstet 20: 91-9 7, 1982 A study of 240 post-menopausal women receiving Dixarit (clonidine hydrochloride), Premarin (conjugated equine oestrogens), Harmogen (piperazine oestrone sulphate) and Progynova (oestradiol valerate) in two different dosages alone and in combination with progestational agents such as norethisterone acetate, dydrogesterone, and norgestrel for climacteric symptoms showed that there was no adverse effect on serum lipid levels. There was no significant change in the serum cholesterol and triglyceride levels during treatment with oestrogen replacement therapy.
Key words: Dixarit ; Premarin;
Progestational agents; Norethisterone acetate; Serum lipid levels; Serum cholesterol; Triglyceride levels; Oestrogen replacement therapy.
Introduction Possible benefits and drawbacks of hormone replacement therapy (HRT) for postwomen menopausal have been widely 0020-7292/82/0000-0000/$02.75
0 1982 International
Federation of Gynaecology & Obstetrics
debated. A comprehensive review of all the available literature would be difficult, but the reports of international symposia held in London during 1975, in La Grand Motte in France during 1978, and in Sheffield during 1978 demonstrate the spectrum of current opinion [ 23,181. Difficulties can arise in the interpretation of data from HRT studies: sometimes synthetic oestrogen compounds are compared with “natural” oestrogens [9 I. The reports so far show that the effect of “natural oestrogen” on lipid metabolism in post-menopausal women receiving oestrogen therapy is variable. Robinson and Lebeau [ 151 claimed that there was a reduction in serum cholesterol and a slight rise in the serum triglyceride levels following treatment with Premarin (conjugated equine oestrogens). Furman et al. [7] also stated that Premarin produced a slight rise in triglyceride levels and the levels of serum cholesterol were variable. Bolton [ 11, Varma [ 191, and Walter and Jensen [ 211 also showed that there were no adverse effects on serum lipid levels when “natural oestrogen” was used for replacement therapy. Recent surveys by the Royal College of Obstetricians and Gynaecologists [ 111 showed that there were no gross changes in the levels of blood lipids during the treatment with natural oestrogens such as conjugated oestrone sulphate, piperazine oestrone sulphate, and oestradiol valerate. There is considerable interest in the effects of hyperlipidemia on the incidence of Int J Gynaecol Obstet 20
92
Varma and Morsman
coronary heart disease (CHD), and it has been well established that hyperlipidemia is a risk factor, along with smoking and hypertension, in the development of CHD in men. This link has been established in post-menopausal women. A number of epidemiological studies [8] have shown that women after the age of 45 are more susceptible to hyperlipidemia and CHD. Noble [ 141 and Carlson and Bottiger [ 31 showed that hyperlipidemia occurs in women around and after the menoincreases in pause, with post-menopausal serum lipid levels amounting to as much as 20% of the pre-menopausal levels. These studies, establishing that there is an increased incidence of CHD in women at the menopause associated with hyperlipidemia, have led to interest in the effects of hormone replacement therapy on serum lipids. Carvalho et al. [4] have suggested that oestrogens may affect the catabolism of lipids by reducing lipoprotein lipase, leading to increased plasma triglycerides and phospholipids. Much of the earlier work on the metabolic effect of oestrogen was carried out on premenopausal women taking oral contraceptives containing synthetic oestrogen [ 10,12,16,17, 221. Of the “natural oestrogen”, the effect of conjugated equine oestrogens (Premarin) on serum lipids was better known than the effects of other estrogen derivatives such as oestradiol valerate (Progynova) and piperazine sulphate (Harmogen) and also oestrone various combinations of oestrogen and progestational agents which are widely in use at present in menopausal clinics in this country. The present study was planned to provide additional information on the effects of oestrogen replacement therapy on blood lipids in post-menopausal women using different regimens of oestrogen and oestrogen/ progesterone combinations. Methods and patients The study group consisted of 240 patients with climacteric symptoms. This group consisted of 140 patients who had a spontaneous Int J Gymecol
Obstet 20
menopause and 100 patients had hysterectomy and bilateral salpingo-oophorectomy for benign pelvic disease. Their ages ranged between 40 years and 65 years (mean 55.5 years) and the time that had elapsed since the menopause varied from 1 year to 25 years (mean 5.2 years). The main climacteric symptoms included hot flushes, night sweats, insomnia and dyspareunia. Serum gonadotrophin levels and oestradiol levels confirmed severe oestrogen deficiency status on all patients. Patients had no steroidal treatment prior to entry into the study. All patients were seen in our special “Menopause” clinic. In addition to all the routine investigations, blood was taken at 9 a.m. prior to treatment and at 3-monthly intervals and 2 weeks after completing each course of a regimen for assessment of cholesterol and triglyceride levels, following a period of fasting from midnight. Blood lipids were assayed using enzymatic methods. The patients were then divided into 3 groups, each group consisting of 80 patients. The mean age, the mean time that had elapsed after attaining the menopause, the number of patients who had spontaneous menopause, the number who had bilateral oophorectomy, the mean weight, and the mean blood pressure were comparable for the three groups (Table I). Table I. Shows the details of the patients groups A, B and C. Details of the patients Mean age (years) Time after menopause (Yea=) Patients who had spontaneous menopause Patients who had bilateral oophorectomy Mean weight (kg) Mean blood pressure (mmHg)
in the three
Group A Group B
Group C
56.8
55.2
55.5
5.1
5.3
5.2
45
41
48
32 62.1
34 64.1
34 63.5
120 18
128 80
126 82
b’fyect of progesterone
Group A
Patients in Group A initially received 0.05 mg of clonidine hydrochloride (Dixarit) twice daily for 6 months. Dixarit is a nonhormonal agent which relieves the vasomotor symptoms and this drug was used as a control being a non-steroidal agent. This regimen was followed by conjugated equine oestrogens (Premarin) in two different dosages and in combination with progestational agents. Dixarit was followed by 0.625 mg of Premarin for 3 out of 4 weeks for 6 months followed by 0.625 mg of Premarin along with 5 mg of norethisterone acetate for 7 days, 10 mg of dydrogesterone for 7 days and 0.5 mg of Norgestrel for 7 days during the third week of the cyclical regimen, each regimen lasting for 6 months. The regimen was then repeated using 1.25 mg of Premarin alone and in combination with each of the above mentioned progestational agents, each course lasting for 6 months. No treatment was given for 4 weeks between each regimen of treatment. Group B Patients in Group B initially received 0.05 mg of clonidine hydrochloride (Dixarit) twice daily for a period of 6 months. Following the course of Dixarit for 6 months, patients received 1.5 mg of Harmogen alone for 3 out of 4 weeks for 6 months followed by 1.5 mg of Harmogen with norethisterone acetate (5 mg for 7 days) during the third week of the 21 day course for 6 months, followed by 1.5 mg of Harmogen with dydrogesterone (10 mg for 7 days) during the third week of the 21 day course for 6 months, followed by 3 more courses, each lasting for 6 months using 2.25 mg of Harmogen alone and in combination with 5 mg of norethisterone acetate and 10 mg dydrogesterone. No treatment was given for 4 weeks between each regimen of treatment. Group C Patients
in
Group
C
initially
received
on post-menopausal women
93
0.05 mg of Dixarit twice daily for 6 months followed by oestradiol valerate (Progynova) in two different dosages alone and in combination with different progestational agents, each course lasting for 6 months with a wash-out period of 4 weeks in between. Patients received 1.0 mg of Progynova alone for 3 out of 4 weeks for 6 months followed by combined treatment with 5 mg of norethisterone for 1 week during the third week of the regimen for 6 months, followed by 10 mg of dydrogesterone for 7 days during the third week of the regimen for 6 months followed by 0.5 mg of norgestrel during the last 10 days of the regimen for 6 months. The cyclical regimen was then repeated using 2 mg of Progynova alone for 6 months followed by combinations of 2 mg of Progynova and the three progestational agents, 5 mg of norethisterone acetate for 7 days, 10 mg of dydrogesterone for 7 days and 0.5 mg of norgestrel for 10 days, each course lasting for 6 months. Serum lipids were assayed before each course of treatment, and at 11 weeks and at 23 weeks while patients were on the treatment, and at 2 weeks after the completion of the 6-monthly regimen. Results All 240 patients had elevated pituitary gonadotrophin levels (FSH) 3-6 times higher than the highest level usually found during a normal menstrual cycle. Serum oestradiol levels were variable but were either at or below the level usually found during the early follicular phase of the menstrual cycle. Tables II and III show the mean and 2 standard deviations (S.D.) for serum cholesterol and triglyceride levels respectively in the three groups of patients (A,B,C) using different dosages and types of oestrogen alone and in combination with three progestational agents. Serum cholesterol There is no significant
difference
in the
Int J Gynaecol Ohstet 20
94
Varma and Morsman
Table II. Mean serum triglyceride levels for each treatment group before, during, and after Dixarit and hormone replacement therapy. Therapy group
Serum triglyceride levels (mmol/l) Post-treatment
Pre-treatment
Treatment
Mean
2 SD.
11 weeks Mean 2 SD.
23 weeks Mean 2 SD.
Mean
Group A Dixarit EO (0.625 mg) EO + NA EO +Dg EO + Ng EO (1.25 mg) EO+NA EO+Dg EO + Ng
1.56 1.56 1.54 1.50 1.56 1.58 1.52 1.50 1.58
* f f f f f f * *
0.34 0.28 0.26 0.21 0.24 0.22 0.21 0.19 0.24
1.60 1.62 1.26 1.34 1.20 1.60 1.38 1.48 1.42
+ f f f f + + f f
0.25 0.26 0.24 0.22 0.21 0.26 0.19 0.22 0.24
1.58 1.60 1.18 1.22 1.16 1.58 1.30 1.42 1.30
+_0.31 * 0.28 f 0.21 f 0.22 + 0.24 f 0.21 f 0.16 r 0.18 f 0.12
1.60 1.64 1.58 1.52 1.40 1.62 1.54 1.40 1.52
f. 0.34 + 0.36 + 0.21 + 0.16 * 0.14 f 0.18 f 0.14 + 0.12 f 0.16
Group B Dixarit ElS (1.5 mg) ElS + NA ElS + Dg ElS (2.25 mg) ElS + NA ElS + Dg
1.54 1.56 1.52 1.48 1.52 1.56 1.55
f * f f f + *
0.24 0.21 0.24 0.24 0.26 0.23 0.24
1.58 1.52 1.42 1.40 1.58 1.40 1.48
f 0.21 ?r0.24 f 0.22 f 0.20 + 0.21 + 0.19 f 0.18
1.56 1.50 1.34 1.28 1.60 1.32 1.28
f f f * f + f
0.22 0.26 0.22 0.14 0.24 0.14 0.12
1.60 1.54 1.52 1.30 1.58 1.57 1.28
f f f 2 f f *
1.56 1.54 1.52 1.58 1.50 1.54 1.58 1.58 1.54
f 0.21 * 0.26 + 0.24 * 0.22 f 0.20 f 0.21 + 0.22 f 0.21 f 0.20
1.60 1.58 1.44 1.32 1.42 1.58 1.42 1.34 1.28
+ 0.22 + a.21 f 0.19 f 0.16 * 0.18 f 0.21 f 0.18 f 0.14 f 0.12
1.62 1.60 1.34 1.28 1.36 1.60 1.26 1.28 1.26
f f + f * * 2 f 2
0.24 0.21 0.12 0.12 0.13 0.18 0.11 0.12 0.10
1.54 1.52 1.52 1.26 1.52 1.54 1.36 1.32 1.37
?I0.21 f 0.19 + 0.21 ? 0.10 * 0.16 f 0.17 f 0.12 * 0.11 + 0.10
Group C Dixarit E2(lmg) E2 + NA E2 + Dg E2 + Ng E2 (2 mg) E2+NA E2 + Dg E2 + Ng
2 SD.
0.26 0.22 0.21 0.14 0.21 0.19 0.11
Abbreviations: EO, Premarin: conjugated equine oestrogen; ElS, Harmogen: piperazine oestrone oestradiol valerate; NA, Norethisterone-acetate; Dg, Dydrogesterone; Ng, Norgestrel.
levels of serum cholesterol in the 240 women taking Dixarit or oestrogen alone. In general, there is no obvious change in the serum cholesterol levels when oestrogen alone was given on a cyclical regimen. The serum cholesterol level at 23 weeks during the treatment was lower as compared with the pre-treatment level when a progestational agent was added for 7 days. The difference between the preInt J Gynaecol Obstet 20
sulphate; E2, Progynova:
treatment level and treatment level was significant, when a progestational agent was added, as compared with the difference in levels when any oestrogen or Dixarit was given (P < 0.05). Of the 80 who received 1.25 of Premarine alone, four developed serum cholesterol levels above the normal range (7.6 mmol/l). However, none of the patients who received pro-
Effect
Table
III.
Mean
cholesterol
levels
for each
treatment
group
before,
of progesterone
during,
and
after
on post-menopausal Dixarit
and
women
hormone
95
replacement
therapy. Therapy
group
Serum cholesterol
levels (mmol/l)
Pre-treatment
Treatment
Mean
2 S.D.
11 weeks Mean 2 S.D.
23 weeks Mean 2 SD.
Mean
5.75 t 5.65 * 5.70 * 5.75 ? 5.60 * 5.58+ 5.60 * 5.65 * 5.50 +
0.98 0.88 0.91 1.01 0.96 1.02 1.03 0.98 0.92
5.80 5.75 5.60 5.60 5.45 5.65 5.35 5.30 5.20
5.60 5.80 5.45 5.40 5.20 5.70 5.25 5.20 5.15
i c f + f * f * *
0.88 0.98 0.86 0.84 0.92 0.91 0.88 0.92 0.86
5.70 5.75 5.80 5.55 5.45 5.65 5.70 5.45 5.65
+ 0.92 * 0.94 * 1.02 t 0.92 ?r0.86 f 0.84 * 0.92 k 0.81 * 0.82
5.70 5.15 5.70 5.75 5.40 5.65 5.60
* * * t f f f
0.88 0.96 0.99 0.95 0.86 0.94 1.01
5.75 f 5.78 * 5.60 fr 5.70 f 5.60* 5.30+ 5.40?
5.80 5.85 5.21+ 5.40 5.75 5.14 5.20
+ 0.94 f 1.01 0.96 * 0.88 * 0.86 * 0.84 fr 0.88
5.75 5.80 5.78 5.35 5.70 5.68 5.30
i 0.81 i 0.88 + 0.92 ?: 0.91 ?: 1.02 f 1.01 f. 0.86
5.40 5.55 5.75 5.65 5.30 5.55 5.65 5.50 5.45
f. i ? f f f t * *
0.88 0.82 0.86 1.01 0.90 0.94 0.84 0.88 0.88
5.55 5.75 5.65 5.50 5.20 5.65 5.35 5.30 5.20
5.60 5.85 5.30 5.20 5.05 5.15 5.10 5.20 5.05
f f f f ? t + + +
5.72 5.80 5.70 5.25 5.50 5.70 5.35 5.30 5.60
?: 1.01 ?: 0.94 + 1.02 + 0.98 f 0.86 ?: 0.81 f 0.84 + 0.84 * 0.85
Post-treatment 2 S.D.
GroupA Dixarit LO (0.625 mg) EO+NA EO + Dg EO + Ng EO (1.25 mg) EO + NA EO + Dg EO + Ng Group B Dixarit ElS (1.5 mg) tlS + NA ElS + Dg ElS EIS ElS ElS
(2.25 mg) + NA + Dg + Ng
Group C Dixarit E2 E2 E2 E2
(1 ms) + NA + Dg + Ng
E2 E2 E2 E2
(2 mg) + NA + Dg + Ng
Abbreviations: EO, Premarin: conjugated oestradiol valerate; NA, Norethisterone-acetate;
f 0.98 _+0.88 + 0.92 f 0.95 r 0.84 i 0.92 + 0.88 f 0.86 + 0.85
0.92 0.90 0.92 0.88 0.86 0.92 0.92
* 0.91 i 0.96 * 0.94 * 0.88 f 0.96 fr 1.01 f 0.84 + 0.94 f: 0.94
0.88 0.96 0.96 0.94 0.94 0.86 1.02 1.01 0.94
EIS, Harmogen: piperazine equine oestrogen; Dg, Dydrogesterone; Ng, Norgestrel.
gestational agents with Premarin developed lipid levels above the normal range. Five out of 80 patients who received 2.25 mg of Harmogen developed raised whereas none of the cholesterol levels, who had progestational agents patients developed high levels of serum cholesterol. Five out of 80 patients who received 2 mg of Progynova also developed open raised
oestrone
sulphate;
E2, Progynova:
serum cholesterol levels and two of those who had Progynova and norgestrel and two patients who had Progynova and norethisterone acetate also had raised levels of serum cholesterol. Only two patients required low fat diet to reduce cholesterol levels and the rest had normal levels of cholesterol when the treatment stopped. Int J Gynaecol
Obstet 20
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Varma and Morsman
Serum trygliceride
There was no significant difference in the levels of serum triglyceride levels when the patients were receiving Dixarit or oestrogen alone. However, the differences between the pre-treatment and treatment levels were significant when a progestational agent was added to the oestrogen replacement therapy, as compared with the differences in the two levels when Dixarit or oestrogen alone was given (P < 0.05). Six of 80 patients on Premarin alone, five of 80 patients on Harmogen alone, and six of 80 patients on Progynova alone developed a rise in triglyceride levels (above 2.8 mmol/l). Only two needed fat-free diets and the rest had normal triglyceride levels once the treatment was stopped. However, none of the patients developed a high triglyceride level while they received an oestrogen/progesterone combination. Discussion
The effect of oestrogen therapy on serum cholesterol and tryglyceride levels in postmenopausal women is still uncertain. There is no unanimity in the reports on the effect on lipids in post-menopausal women receiving oestrogen replacement therapy. Bolton [ 11, Villadolid et al. [ 201, Walter and Jensen 12 11, Maddock [13], Varma [19], and the recent study done by the Royal College of Obstetricians and Gynaecologists [ 11 I showed that the blood lipid levels were not adversely affected by oestrogen replacement therapy. We studied a total number of 240 patients divided into three groups receiving 23 different regimens of treatment for a period of 6 months. There was a small but statistically significant decrease in cholesterol in the 240 patients taking HRT when analysed as a single group as compared with the reduction in the Dixarit group (P< 0.05). The reduction in level was higher in the group who received an oestrogen/progesterone combination as compared with those who had only oestrogen (P < 0.0 1). Int J Gynaecol Obstet 20
There was no significant change in triglyceride concentration when the patients on HRT were taken as a group as compared with the level in the Dixarit. The fall in triglyceride level in the group who received oestrogen and progesterone combination was higher as compared with those who received only oestrogen (P < 0.0 I). In menstruating women, there is mounting suspicion that the contraceptive pill increased the incidence of myocardial infarction. However, the relationship between the menopause, coronary artery disease, hyperlipidemia and oestrogen replacement therapy is still not clear [6]. It would be paradoxical if on the one hand, women losing their ovarian function should become more prone to coronary heart disease and on the other hand, that oestrogen replacement therapy might be raising the level of blood lipids, itself proving an additional adverse factor. Our study of 240 patients using different dosages and types of oestrogen alone or in combination with progestational agents on a cyclical regimen does not show that hormone replacement therapy leads to hyperlipidemia. Addition of progestational agents such as dydrogesterone did appear to reduce both cholesterol and triglyceride levels. Acknowledgement
I would like to thank Professor R.R. Trussell for his support in organizing this study, and also Professor J.A. Owen and his colleagues for dosing the assays of blood lipids. My special thanks to my Junior Colleagues and Nursing staff who made this study possible, and to my secretary Mrs. Christine Murdock for her invaluable help in organizing the data and the paper. References Bolton CH: The effects of ethinyl estiadiol and conjugated equine estrogens on plasma lipids in oophoectomized women. In The Management of the Menopause and Post-menopausal Years(ed Stuart Campbell), p. 185, M.T.P. Press Ltd., 1975.
Effect of progesterone
2 Campbell S: The Management of the Menopause and Post-Menopausal Years. M.T.P. Press, Ltd., Lancaster, 1976. 3 Carlson LA, Bottiger LE: Ischaemic heart disease in relation to fasting values of plasma triglycerides and cholesterol. Stockholm Prospective Study. Lancet I: 865. 1972. 4 Carvalho AGA. Vaillancourt RA, Cabral RA, Lees RJ: Coagulation abnormalities in women taking oral contraceptives. J Am Med Assoc 237: 875, 1977. 5 Cooke ID: The Role of Oestrogens/Progestogens in the llanagement of the Menopause. M.T.P. Press Ltd., Lancaster, 1978. 6 Editorial: Oestrogens, lipids and gall stones. Br Med J 1. 132. 1974. 7 I urman RH. Alaupovic P, Howard RP: Effect of androgem and estrogens on serum lipids and the composition of and the concentrations of serum lipoproteins in normolipemic and hyperlipidemic states. Prog Biochem PharmacolZ: 215, 1967. 8 lnman WH, Vessey MP, Westerholme B, Engelund A: Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 2: 203, 1970. 9 Jones MM, Marshall DH, Nordin BEC; Curr Med Res. opin 4: Suppl. 3, 12, 1977. 10 Larsson-Cohn U, Berlin R, Vikrot 0: Effects of combined and low dose gestagen oral contraceptives on plasma lipids, including individual phospholipids. Acta Endocrinol (kbh) 63: 717,197O. 11 Lind T, Cameron EC, Hunter WM et al.: A prospective controlled trial of six forms of hormone replacement therapy given to post-menopausal women. Br J Obstet Gynaecol86: Suppl. 3, 1979. 12 Lunell NO, Persson B, Ohquist G: The effects of an oral combined contraceptive on plasma levels of flucose, free fatty acids, glycerol, D. hydroxybutyvate and triglycerides. Acta Obstet Gynecol Stand 52: 23, 1973.
on post-menopausal
women
97
13 Maddock J: Effects of progestogens on serum lipid in the post-menopause. Postgrad Med J 54: (suppl. 2) 38, 1978. 14 Noble RP: Electrophoretic plasma lipoproteins in agarose gel. J Lipid Res 9: 693, 1968. 15 Robinson RW, Lebeau RJ: Effect of conjugated equine estrogens on serum lipids and the clotting mechanisms. J Atheroscl. Res. 5: 120, 1965. 16 Spellacy WN, Buhi WC, Birk SA, Cabal R: The effects of oestrogens and progestogens, oral contraceptives and intrauterine devices on fasting triglyceride and insulin levels. Fertil Steril24: 178, 1973. 17 Stokes T, Wynn V: Serum lipids in women on oral contraceptives Lancet 2: 677, 1971. 18 Van Keep PA, Greenblatt RB, Albeaux-Fernet M: Consensus on Menopause Research. M.T.P. Press Ltd, Lancaster, 1976. 19 Varma TR: Effect of estrogen on fasting serum cholesterol and triglyceride levels in post-menopausal women. Int J Obstet Gynaecol 17(6): 55, 1980. 20 Villadolid LS, Buenaluz L, Iledan A: Progress report on long-term oestrogen therapy. Cun Med Res Opin 1: 577, 1973. 21 Walter S, Jensen HK: The effect of treatment with oestradiol and oestriol on fasting serum cholesterol and triglyceride levels in post-menopausal women. Br J Obstet Gynaecol84: 869, 1977. 22 Wynn V, Dear JWH, Mills GL, Stokes T: Fasting serum triglyceride, cholesterol and lipoprotein levels during oral contraceptive therapy, Lancet 2: 756, 1969.
Address for reprints:
T.R. Varma St. George’s Hospital Cranmer Terrace London SW17 ORE UK
Int J Gynaecol Obstet 20
International
91-97
Federation of Gynaecology & Obstetrics
EFFECT OF OESTROGEN AND PROGESTERONE ON FASTING SERUM CHOLESTEROL AND TRIGLYCERIDE LEVELS IN POST-MENOPAUSAL WOMEN
T.R. VARMA and JOHN MORSMAN St. George’s Hospital, Cranmer Terrace, London SW1 7
ORE, UK
(Received May 21st, 1981) (Accepted July 9th, 1981)
Abstract Varma TR, Morsman J (St. George’s Hospital, Cranmer Terrace, London SW1 7 ORE, UK). Effect of oestrogen and progesterone on fasting serum cholesterol and triglyceride levels in post-menopausal women. Int J Gynaecol Obstet 20: 91-9 7, 1982 A study of 240 post-menopausal women receiving Dixarit (clonidine hydrochloride), Premarin (conjugated equine oestrogens), Harmogen (piperazine oestrone sulphate) and Progynova (oestradiol valerate) in two different dosages alone and in combination with progestational agents such as norethisterone acetate, dydrogesterone, and norgestrel for climacteric symptoms showed that there was no adverse effect on serum lipid levels. There was no significant change in the serum cholesterol and triglyceride levels during treatment with oestrogen replacement therapy.
Key words: Dixarit ; Premarin;
Progestational agents; Norethisterone acetate; Serum lipid levels; Serum cholesterol; Triglyceride levels; Oestrogen replacement therapy.
Introduction Possible benefits and drawbacks of hormone replacement therapy (HRT) for postwomen menopausal have been widely 0020-7292/82/0000-0000/$02.75
0 1982 International
Federation of Gynaecology & Obstetrics
debated. A comprehensive review of all the available literature would be difficult, but the reports of international symposia held in London during 1975, in La Grand Motte in France during 1978, and in Sheffield during 1978 demonstrate the spectrum of current opinion [ 23,181. Difficulties can arise in the interpretation of data from HRT studies: sometimes synthetic oestrogen compounds are compared with “natural” oestrogens [9 I. The reports so far show that the effect of “natural oestrogen” on lipid metabolism in post-menopausal women receiving oestrogen therapy is variable. Robinson and Lebeau [ 151 claimed that there was a reduction in serum cholesterol and a slight rise in the serum triglyceride levels following treatment with Premarin (conjugated equine oestrogens). Furman et al. [7] also stated that Premarin produced a slight rise in triglyceride levels and the levels of serum cholesterol were variable. Bolton [ 11, Varma [ 191, and Walter and Jensen [ 211 also showed that there were no adverse effects on serum lipid levels when “natural oestrogen” was used for replacement therapy. Recent surveys by the Royal College of Obstetricians and Gynaecologists [ 111 showed that there were no gross changes in the levels of blood lipids during the treatment with natural oestrogens such as conjugated oestrone sulphate, piperazine oestrone sulphate, and oestradiol valerate. There is considerable interest in the effects of hyperlipidemia on the incidence of Int J Gynaecol Obstet 20
92
Varma and Morsman
coronary heart disease (CHD), and it has been well established that hyperlipidemia is a risk factor, along with smoking and hypertension, in the development of CHD in men. This link has been established in post-menopausal women. A number of epidemiological studies [8] have shown that women after the age of 45 are more susceptible to hyperlipidemia and CHD. Noble [ 141 and Carlson and Bottiger [ 31 showed that hyperlipidemia occurs in women around and after the menoincreases in pause, with post-menopausal serum lipid levels amounting to as much as 20% of the pre-menopausal levels. These studies, establishing that there is an increased incidence of CHD in women at the menopause associated with hyperlipidemia, have led to interest in the effects of hormone replacement therapy on serum lipids. Carvalho et al. [4] have suggested that oestrogens may affect the catabolism of lipids by reducing lipoprotein lipase, leading to increased plasma triglycerides and phospholipids. Much of the earlier work on the metabolic effect of oestrogen was carried out on premenopausal women taking oral contraceptives containing synthetic oestrogen [ 10,12,16,17, 221. Of the “natural oestrogen”, the effect of conjugated equine oestrogens (Premarin) on serum lipids was better known than the effects of other estrogen derivatives such as oestradiol valerate (Progynova) and piperazine sulphate (Harmogen) and also oestrone various combinations of oestrogen and progestational agents which are widely in use at present in menopausal clinics in this country. The present study was planned to provide additional information on the effects of oestrogen replacement therapy on blood lipids in post-menopausal women using different regimens of oestrogen and oestrogen/ progesterone combinations. Methods and patients The study group consisted of 240 patients with climacteric symptoms. This group consisted of 140 patients who had a spontaneous Int J Gymecol
Obstet 20
menopause and 100 patients had hysterectomy and bilateral salpingo-oophorectomy for benign pelvic disease. Their ages ranged between 40 years and 65 years (mean 55.5 years) and the time that had elapsed since the menopause varied from 1 year to 25 years (mean 5.2 years). The main climacteric symptoms included hot flushes, night sweats, insomnia and dyspareunia. Serum gonadotrophin levels and oestradiol levels confirmed severe oestrogen deficiency status on all patients. Patients had no steroidal treatment prior to entry into the study. All patients were seen in our special “Menopause” clinic. In addition to all the routine investigations, blood was taken at 9 a.m. prior to treatment and at 3-monthly intervals and 2 weeks after completing each course of a regimen for assessment of cholesterol and triglyceride levels, following a period of fasting from midnight. Blood lipids were assayed using enzymatic methods. The patients were then divided into 3 groups, each group consisting of 80 patients. The mean age, the mean time that had elapsed after attaining the menopause, the number of patients who had spontaneous menopause, the number who had bilateral oophorectomy, the mean weight, and the mean blood pressure were comparable for the three groups (Table I). Table I. Shows the details of the patients groups A, B and C. Details of the patients Mean age (years) Time after menopause (Yea=) Patients who had spontaneous menopause Patients who had bilateral oophorectomy Mean weight (kg) Mean blood pressure (mmHg)
in the three
Group A Group B
Group C
56.8
55.2
55.5
5.1
5.3
5.2
45
41
48
32 62.1
34 64.1
34 63.5
120 18
128 80
126 82
b’fyect of progesterone
Group A
Patients in Group A initially received 0.05 mg of clonidine hydrochloride (Dixarit) twice daily for 6 months. Dixarit is a nonhormonal agent which relieves the vasomotor symptoms and this drug was used as a control being a non-steroidal agent. This regimen was followed by conjugated equine oestrogens (Premarin) in two different dosages and in combination with progestational agents. Dixarit was followed by 0.625 mg of Premarin for 3 out of 4 weeks for 6 months followed by 0.625 mg of Premarin along with 5 mg of norethisterone acetate for 7 days, 10 mg of dydrogesterone for 7 days and 0.5 mg of Norgestrel for 7 days during the third week of the cyclical regimen, each regimen lasting for 6 months. The regimen was then repeated using 1.25 mg of Premarin alone and in combination with each of the above mentioned progestational agents, each course lasting for 6 months. No treatment was given for 4 weeks between each regimen of treatment. Group B Patients in Group B initially received 0.05 mg of clonidine hydrochloride (Dixarit) twice daily for a period of 6 months. Following the course of Dixarit for 6 months, patients received 1.5 mg of Harmogen alone for 3 out of 4 weeks for 6 months followed by 1.5 mg of Harmogen with norethisterone acetate (5 mg for 7 days) during the third week of the 21 day course for 6 months, followed by 1.5 mg of Harmogen with dydrogesterone (10 mg for 7 days) during the third week of the 21 day course for 6 months, followed by 3 more courses, each lasting for 6 months using 2.25 mg of Harmogen alone and in combination with 5 mg of norethisterone acetate and 10 mg dydrogesterone. No treatment was given for 4 weeks between each regimen of treatment. Group C Patients
in
Group
C
initially
received
on post-menopausal women
93
0.05 mg of Dixarit twice daily for 6 months followed by oestradiol valerate (Progynova) in two different dosages alone and in combination with different progestational agents, each course lasting for 6 months with a wash-out period of 4 weeks in between. Patients received 1.0 mg of Progynova alone for 3 out of 4 weeks for 6 months followed by combined treatment with 5 mg of norethisterone for 1 week during the third week of the regimen for 6 months, followed by 10 mg of dydrogesterone for 7 days during the third week of the regimen for 6 months followed by 0.5 mg of norgestrel during the last 10 days of the regimen for 6 months. The cyclical regimen was then repeated using 2 mg of Progynova alone for 6 months followed by combinations of 2 mg of Progynova and the three progestational agents, 5 mg of norethisterone acetate for 7 days, 10 mg of dydrogesterone for 7 days and 0.5 mg of norgestrel for 10 days, each course lasting for 6 months. Serum lipids were assayed before each course of treatment, and at 11 weeks and at 23 weeks while patients were on the treatment, and at 2 weeks after the completion of the 6-monthly regimen. Results All 240 patients had elevated pituitary gonadotrophin levels (FSH) 3-6 times higher than the highest level usually found during a normal menstrual cycle. Serum oestradiol levels were variable but were either at or below the level usually found during the early follicular phase of the menstrual cycle. Tables II and III show the mean and 2 standard deviations (S.D.) for serum cholesterol and triglyceride levels respectively in the three groups of patients (A,B,C) using different dosages and types of oestrogen alone and in combination with three progestational agents. Serum cholesterol There is no significant
difference
in the
Int J Gynaecol Ohstet 20
94
Varma and Morsman
Table II. Mean serum triglyceride levels for each treatment group before, during, and after Dixarit and hormone replacement therapy. Therapy group
Serum triglyceride levels (mmol/l) Post-treatment
Pre-treatment
Treatment
Mean
2 SD.
11 weeks Mean 2 SD.
23 weeks Mean 2 SD.
Mean
Group A Dixarit EO (0.625 mg) EO + NA EO +Dg EO + Ng EO (1.25 mg) EO+NA EO+Dg EO + Ng
1.56 1.56 1.54 1.50 1.56 1.58 1.52 1.50 1.58
* f f f f f f * *
0.34 0.28 0.26 0.21 0.24 0.22 0.21 0.19 0.24
1.60 1.62 1.26 1.34 1.20 1.60 1.38 1.48 1.42
+ f f f f + + f f
0.25 0.26 0.24 0.22 0.21 0.26 0.19 0.22 0.24
1.58 1.60 1.18 1.22 1.16 1.58 1.30 1.42 1.30
+_0.31 * 0.28 f 0.21 f 0.22 + 0.24 f 0.21 f 0.16 r 0.18 f 0.12
1.60 1.64 1.58 1.52 1.40 1.62 1.54 1.40 1.52
f. 0.34 + 0.36 + 0.21 + 0.16 * 0.14 f 0.18 f 0.14 + 0.12 f 0.16
Group B Dixarit ElS (1.5 mg) ElS + NA ElS + Dg ElS (2.25 mg) ElS + NA ElS + Dg
1.54 1.56 1.52 1.48 1.52 1.56 1.55
f * f f f + *
0.24 0.21 0.24 0.24 0.26 0.23 0.24
1.58 1.52 1.42 1.40 1.58 1.40 1.48
f 0.21 ?r0.24 f 0.22 f 0.20 + 0.21 + 0.19 f 0.18
1.56 1.50 1.34 1.28 1.60 1.32 1.28
f f f * f + f
0.22 0.26 0.22 0.14 0.24 0.14 0.12
1.60 1.54 1.52 1.30 1.58 1.57 1.28
f f f 2 f f *
1.56 1.54 1.52 1.58 1.50 1.54 1.58 1.58 1.54
f 0.21 * 0.26 + 0.24 * 0.22 f 0.20 f 0.21 + 0.22 f 0.21 f 0.20
1.60 1.58 1.44 1.32 1.42 1.58 1.42 1.34 1.28
+ 0.22 + a.21 f 0.19 f 0.16 * 0.18 f 0.21 f 0.18 f 0.14 f 0.12
1.62 1.60 1.34 1.28 1.36 1.60 1.26 1.28 1.26
f f + f * * 2 f 2
0.24 0.21 0.12 0.12 0.13 0.18 0.11 0.12 0.10
1.54 1.52 1.52 1.26 1.52 1.54 1.36 1.32 1.37
?I0.21 f 0.19 + 0.21 ? 0.10 * 0.16 f 0.17 f 0.12 * 0.11 + 0.10
Group C Dixarit E2(lmg) E2 + NA E2 + Dg E2 + Ng E2 (2 mg) E2+NA E2 + Dg E2 + Ng
2 SD.
0.26 0.22 0.21 0.14 0.21 0.19 0.11
Abbreviations: EO, Premarin: conjugated equine oestrogen; ElS, Harmogen: piperazine oestrone oestradiol valerate; NA, Norethisterone-acetate; Dg, Dydrogesterone; Ng, Norgestrel.
levels of serum cholesterol in the 240 women taking Dixarit or oestrogen alone. In general, there is no obvious change in the serum cholesterol levels when oestrogen alone was given on a cyclical regimen. The serum cholesterol level at 23 weeks during the treatment was lower as compared with the pre-treatment level when a progestational agent was added for 7 days. The difference between the preInt J Gynaecol Obstet 20
sulphate; E2, Progynova:
treatment level and treatment level was significant, when a progestational agent was added, as compared with the difference in levels when any oestrogen or Dixarit was given (P < 0.05). Of the 80 who received 1.25 of Premarine alone, four developed serum cholesterol levels above the normal range (7.6 mmol/l). However, none of the patients who received pro-
Effect
Table
III.
Mean
cholesterol
levels
for each
treatment
group
before,
of progesterone
during,
and
after
on post-menopausal Dixarit
and
women
hormone
95
replacement
therapy. Therapy
group
Serum cholesterol
levels (mmol/l)
Pre-treatment
Treatment
Mean
2 S.D.
11 weeks Mean 2 S.D.
23 weeks Mean 2 SD.
Mean
5.75 t 5.65 * 5.70 * 5.75 ? 5.60 * 5.58+ 5.60 * 5.65 * 5.50 +
0.98 0.88 0.91 1.01 0.96 1.02 1.03 0.98 0.92
5.80 5.75 5.60 5.60 5.45 5.65 5.35 5.30 5.20
5.60 5.80 5.45 5.40 5.20 5.70 5.25 5.20 5.15
i c f + f * f * *
0.88 0.98 0.86 0.84 0.92 0.91 0.88 0.92 0.86
5.70 5.75 5.80 5.55 5.45 5.65 5.70 5.45 5.65
+ 0.92 * 0.94 * 1.02 t 0.92 ?r0.86 f 0.84 * 0.92 k 0.81 * 0.82
5.70 5.15 5.70 5.75 5.40 5.65 5.60
* * * t f f f
0.88 0.96 0.99 0.95 0.86 0.94 1.01
5.75 f 5.78 * 5.60 fr 5.70 f 5.60* 5.30+ 5.40?
5.80 5.85 5.21+ 5.40 5.75 5.14 5.20
+ 0.94 f 1.01 0.96 * 0.88 * 0.86 * 0.84 fr 0.88
5.75 5.80 5.78 5.35 5.70 5.68 5.30
i 0.81 i 0.88 + 0.92 ?: 0.91 ?: 1.02 f 1.01 f. 0.86
5.40 5.55 5.75 5.65 5.30 5.55 5.65 5.50 5.45
f. i ? f f f t * *
0.88 0.82 0.86 1.01 0.90 0.94 0.84 0.88 0.88
5.55 5.75 5.65 5.50 5.20 5.65 5.35 5.30 5.20
5.60 5.85 5.30 5.20 5.05 5.15 5.10 5.20 5.05
f f f f ? t + + +
5.72 5.80 5.70 5.25 5.50 5.70 5.35 5.30 5.60
?: 1.01 ?: 0.94 + 1.02 + 0.98 f 0.86 ?: 0.81 f 0.84 + 0.84 * 0.85
Post-treatment 2 S.D.
GroupA Dixarit LO (0.625 mg) EO+NA EO + Dg EO + Ng EO (1.25 mg) EO + NA EO + Dg EO + Ng Group B Dixarit ElS (1.5 mg) tlS + NA ElS + Dg ElS EIS ElS ElS
(2.25 mg) + NA + Dg + Ng
Group C Dixarit E2 E2 E2 E2
(1 ms) + NA + Dg + Ng
E2 E2 E2 E2
(2 mg) + NA + Dg + Ng
Abbreviations: EO, Premarin: conjugated oestradiol valerate; NA, Norethisterone-acetate;
f 0.98 _+0.88 + 0.92 f 0.95 r 0.84 i 0.92 + 0.88 f 0.86 + 0.85
0.92 0.90 0.92 0.88 0.86 0.92 0.92
* 0.91 i 0.96 * 0.94 * 0.88 f 0.96 fr 1.01 f 0.84 + 0.94 f: 0.94
0.88 0.96 0.96 0.94 0.94 0.86 1.02 1.01 0.94
EIS, Harmogen: piperazine equine oestrogen; Dg, Dydrogesterone; Ng, Norgestrel.
gestational agents with Premarin developed lipid levels above the normal range. Five out of 80 patients who received 2.25 mg of Harmogen developed raised whereas none of the cholesterol levels, who had progestational agents patients developed high levels of serum cholesterol. Five out of 80 patients who received 2 mg of Progynova also developed open raised
oestrone
sulphate;
E2, Progynova:
serum cholesterol levels and two of those who had Progynova and norgestrel and two patients who had Progynova and norethisterone acetate also had raised levels of serum cholesterol. Only two patients required low fat diet to reduce cholesterol levels and the rest had normal levels of cholesterol when the treatment stopped. Int J Gynaecol
Obstet 20
96
Varma and Morsman
Serum trygliceride
There was no significant difference in the levels of serum triglyceride levels when the patients were receiving Dixarit or oestrogen alone. However, the differences between the pre-treatment and treatment levels were significant when a progestational agent was added to the oestrogen replacement therapy, as compared with the differences in the two levels when Dixarit or oestrogen alone was given (P < 0.05). Six of 80 patients on Premarin alone, five of 80 patients on Harmogen alone, and six of 80 patients on Progynova alone developed a rise in triglyceride levels (above 2.8 mmol/l). Only two needed fat-free diets and the rest had normal triglyceride levels once the treatment was stopped. However, none of the patients developed a high triglyceride level while they received an oestrogen/progesterone combination. Discussion
The effect of oestrogen therapy on serum cholesterol and tryglyceride levels in postmenopausal women is still uncertain. There is no unanimity in the reports on the effect on lipids in post-menopausal women receiving oestrogen replacement therapy. Bolton [ 11, Villadolid et al. [ 201, Walter and Jensen 12 11, Maddock [13], Varma [19], and the recent study done by the Royal College of Obstetricians and Gynaecologists [ 11 I showed that the blood lipid levels were not adversely affected by oestrogen replacement therapy. We studied a total number of 240 patients divided into three groups receiving 23 different regimens of treatment for a period of 6 months. There was a small but statistically significant decrease in cholesterol in the 240 patients taking HRT when analysed as a single group as compared with the reduction in the Dixarit group (P< 0.05). The reduction in level was higher in the group who received an oestrogen/progesterone combination as compared with those who had only oestrogen (P < 0.0 1). Int J Gynaecol Obstet 20
There was no significant change in triglyceride concentration when the patients on HRT were taken as a group as compared with the level in the Dixarit. The fall in triglyceride level in the group who received oestrogen and progesterone combination was higher as compared with those who received only oestrogen (P < 0.0 I). In menstruating women, there is mounting suspicion that the contraceptive pill increased the incidence of myocardial infarction. However, the relationship between the menopause, coronary artery disease, hyperlipidemia and oestrogen replacement therapy is still not clear [6]. It would be paradoxical if on the one hand, women losing their ovarian function should become more prone to coronary heart disease and on the other hand, that oestrogen replacement therapy might be raising the level of blood lipids, itself proving an additional adverse factor. Our study of 240 patients using different dosages and types of oestrogen alone or in combination with progestational agents on a cyclical regimen does not show that hormone replacement therapy leads to hyperlipidemia. Addition of progestational agents such as dydrogesterone did appear to reduce both cholesterol and triglyceride levels. Acknowledgement
I would like to thank Professor R.R. Trussell for his support in organizing this study, and also Professor J.A. Owen and his colleagues for dosing the assays of blood lipids. My special thanks to my Junior Colleagues and Nursing staff who made this study possible, and to my secretary Mrs. Christine Murdock for her invaluable help in organizing the data and the paper. References Bolton CH: The effects of ethinyl estiadiol and conjugated equine estrogens on plasma lipids in oophoectomized women. In The Management of the Menopause and Post-menopausal Years(ed Stuart Campbell), p. 185, M.T.P. Press Ltd., 1975.
Effect of progesterone
2 Campbell S: The Management of the Menopause and Post-Menopausal Years. M.T.P. Press, Ltd., Lancaster, 1976. 3 Carlson LA, Bottiger LE: Ischaemic heart disease in relation to fasting values of plasma triglycerides and cholesterol. Stockholm Prospective Study. Lancet I: 865. 1972. 4 Carvalho AGA. Vaillancourt RA, Cabral RA, Lees RJ: Coagulation abnormalities in women taking oral contraceptives. J Am Med Assoc 237: 875, 1977. 5 Cooke ID: The Role of Oestrogens/Progestogens in the llanagement of the Menopause. M.T.P. Press Ltd., Lancaster, 1978. 6 Editorial: Oestrogens, lipids and gall stones. Br Med J 1. 132. 1974. 7 I urman RH. Alaupovic P, Howard RP: Effect of androgem and estrogens on serum lipids and the composition of and the concentrations of serum lipoproteins in normolipemic and hyperlipidemic states. Prog Biochem PharmacolZ: 215, 1967. 8 lnman WH, Vessey MP, Westerholme B, Engelund A: Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 2: 203, 1970. 9 Jones MM, Marshall DH, Nordin BEC; Curr Med Res. opin 4: Suppl. 3, 12, 1977. 10 Larsson-Cohn U, Berlin R, Vikrot 0: Effects of combined and low dose gestagen oral contraceptives on plasma lipids, including individual phospholipids. Acta Endocrinol (kbh) 63: 717,197O. 11 Lind T, Cameron EC, Hunter WM et al.: A prospective controlled trial of six forms of hormone replacement therapy given to post-menopausal women. Br J Obstet Gynaecol86: Suppl. 3, 1979. 12 Lunell NO, Persson B, Ohquist G: The effects of an oral combined contraceptive on plasma levels of flucose, free fatty acids, glycerol, D. hydroxybutyvate and triglycerides. Acta Obstet Gynecol Stand 52: 23, 1973.
on post-menopausal
women
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13 Maddock J: Effects of progestogens on serum lipid in the post-menopause. Postgrad Med J 54: (suppl. 2) 38, 1978. 14 Noble RP: Electrophoretic plasma lipoproteins in agarose gel. J Lipid Res 9: 693, 1968. 15 Robinson RW, Lebeau RJ: Effect of conjugated equine estrogens on serum lipids and the clotting mechanisms. J Atheroscl. Res. 5: 120, 1965. 16 Spellacy WN, Buhi WC, Birk SA, Cabal R: The effects of oestrogens and progestogens, oral contraceptives and intrauterine devices on fasting triglyceride and insulin levels. Fertil Steril24: 178, 1973. 17 Stokes T, Wynn V: Serum lipids in women on oral contraceptives Lancet 2: 677, 1971. 18 Van Keep PA, Greenblatt RB, Albeaux-Fernet M: Consensus on Menopause Research. M.T.P. Press Ltd, Lancaster, 1976. 19 Varma TR: Effect of estrogen on fasting serum cholesterol and triglyceride levels in post-menopausal women. Int J Obstet Gynaecol 17(6): 55, 1980. 20 Villadolid LS, Buenaluz L, Iledan A: Progress report on long-term oestrogen therapy. Cun Med Res Opin 1: 577, 1973. 21 Walter S, Jensen HK: The effect of treatment with oestradiol and oestriol on fasting serum cholesterol and triglyceride levels in post-menopausal women. Br J Obstet Gynaecol84: 869, 1977. 22 Wynn V, Dear JWH, Mills GL, Stokes T: Fasting serum triglyceride, cholesterol and lipoprotein levels during oral contraceptive therapy, Lancet 2: 756, 1969.
Address for reprints:
T.R. Varma St. George’s Hospital Cranmer Terrace London SW17 ORE UK
Int J Gynaecol Obstet 20