105
Int J Gynecol Obstet, 1992, 39: 105-110 International Federation of Gynecology and Obstetrics
The effect of desogestrel for hormone replacement therapy on the blood lipid profiles of postmenopausal women O.P. Tadmora,
Y. Kleinmanb,
aDepartment of Gynecology, ‘Gastroenterology
R. Goldsteinc
Shaare Zedek Medical Center, bMetabolic
Laboratory.
and Y.Z. Diamanta Unit, Department of Internal Medicine. Bikur Cholim Hospital,
Shaare Zedek Medical Center, Jerusalem
(Israel)
(Received December 22nd, 1991) (Revised and accepted March 18th, 1992)
Abstract
Objective: To determine the effect of a hormone replacement protocol containing conjugated equine estrogens and desogestrel (which has a highly selective progestogenic and low androgenic effect) as the progestogen, on the plasma lipid profile, as compared with two other hormone replacement treatments (HRT). Method: Eighty-nine healthy postmenopausal women were divided prospectively into four groups. A control group of 24 women did not receive HRT. Twenty-nine women received conjugated equine estrogen and medroxyprogesterone, and 13 women received a protocol containing estradiol, estriol and norethisterone acetate. Fasting blood lipid was taken at the end of each third cycle. The cumulative therapeutic response was calculated in each group as compared with initial values and between groups. Significance was analyzed by t-tests. Results: A protocol containing desogestrel significantly decreased low-density lipoprotein cholesterol (27%; P < 0.05) and increased high-density lipoprotein cholesterol (HDL-C) by 30% (P < 0.05%) after 9 months. The ratio of total cholesterol to HDLC also decreased significantly (44%; P < 0.05). Conclusion: The most beneficial effect on plasma lipid profile was obtained with an HRT protocol containing desogestrel as the progesterone.
0020-7292/92l~O5.00 0 1992 International
Federation of Gynecology and Obstetrics Printed and Published in Ireland
Keywords: Hormone replacement therapy; Lipoproteins; Desogestrel; Menopause; Cholesterol; High density lipoproteins. Introduction
Estrogen replacement therapy has been shown to reduce low density lipoprotein cholesterol (LDL-C), while increasing high density lipoprotein cholesterol (HDL-C) [9]. However, most progestins increase LDL-C levels and lower HDL-C levels [ 16,181. However, common hormone replacement therapy (HRT) involves cyclical adjustments of estrogen and progestogen because of the increased risk of endometrial carcinoma. There is therefore great concern whether progestogens may offset or neutralize the beneficial effect of estrogen [6]. The body of data presented in the literature is controversial. In many reports progestogen supplementation did not blunt the estrogen LDL-C lowering effect, whereas some progestin products decreased HDL-C to lower than the pretreatment level [ 10,181. Desogesterol, a relatively new progestin, belongs to the third generation of oral contraceptives. It has been shown to have a high relative binding affinity to human progesterone receptors, but a low affinity to human androgen receptors. Desogestrel has been reported to have a Article
106
Tadmor et al.
lipid-beneficial effect, especially on the elevation of APO-AI and HDL2. We have found no studies which compared the efficacy of combinations containing desogestrel among postmenopausal women. Taking advantage of this effect on lowering lipids, we examined the influence of a novel protocol for HRT containing desogestrel on the lipid profile of postmenopausal women. Materials and methods postmenopausal Eighty-nine healthy women attending the Jerusalem Municipal Climacteric Center Clinic and the Shaare Zedek Climacteric Clinic were enrolled in the study. All women had undergone natural or surgical menopause within the last 5 years. Patients were divided into four groups: a control group (24 women who did not receive HRT), a DCEE group which was given conjugated equine estrogens for 15 days and an ethinyl estradiol-desogestrel combination for the next 10 days, as found in the contraceptive pill (29 women); a CEEMPA group, which was given a fixed protocol of conjugated equine estrogens and medroxyprogesterone acetate, marketed under the trade name Premaril Plus (23 women); and an EENA group, which was given a fixed regimen of estradiol, estriol and norethisterone acetate, marketed under the trade name Trisequens (13 women). All of the women had a 1-month
Table 1.
adjustment period, in order to provide and institute the recommended dietary guidelines for the healthy population suggested by the Nutrition Committee of the American Heart Association [ 11. Treatment with HRT was begun after this period. The DCEE group took conjugated equine estrogen (0.625 mg/day) for 15 days and ethinyl estradiol 30 pg together with desogestrel 150 pg for the next 10 days. The EENA group was treated for 28 days per month with a fixed combination of estradiol, estriol and norethisterone acetate, according to the printed dosage: 12 days of estradiol 2 mg and estriol 1 mg; 10 days of estradiol 2 mg, estriol 1 mg and norethisterone acetate 1 mg; and 6 days of estradiol 1 mg and estriol 0.5 mg. The CEEMPA group was treated for 25 days with conjugated equine estrogens 0.625 mg. Medroxyprogesterone acetate 5 mg was added from Day 13 to Day 25. Study medications were offered free of charge and patients were examined every 3 months for adverse effects. Compliance to therapy was checked by pill counting. The control group was monitored in the clinic, but the women did not receive HRT. The blood lipids profile (total cholesterol TC, LDL-C, HDL-C and triglycerides TG) was determined at the beginning of the study, after 1 month of lifestyle adjustment, and at 3-month intervals, for g-months.
Physical characteristics of the subjects in the three groupsa.
Characteristics
DCEE (n = 29)
Age (years) Weight (kg) Height (cm) Body Mass Index (kp/m*) Menopause period (years)
54 f 66.9 zt 160.8 zt 25.4 zt 3*
1.5 5.1 4.5 2.9 0.7
CEEMPA (n = 23)
EENA (n = 13)
56 ZIZ1 66.4 zt 6.3 161.3 zt 3.1 25.5 zt 2.6 5 * 1.0
53 f 67.5 zt 161.9 f 25.8 f 3f
Control (n = 24) 1 7.5 6.5 2.7 1.0
53 * 65.9 zt 160.9 f 25.4 f 4+0
P value*
1 10.4 6.9 2.8
ns ns ns ns ns
aPlus/minus values are mean * SEM for continuous variables. *P values are for comparisons among the three groups by analysis of variance. CEEMPA, conjugated equine estrogens and medroxy progesterone acetate; EENA, estradiol, estriol and norethisterone acetate; DCEE, conjugated equine estrogens and 10 days of ethinyl estradiol+ desogestrel; ns, not significant. Int J Gynecol Obstet 39
Effect of desogestrelfor HRT
Table 2.
101
Changes in blood lipids in the three groups before and after 9 monthsa. Control
TC TG HDL-C LDL-C
CEEMPA
DCEE
Before
After
Before
After
224 f 14 136 f 12 42 f 2.0 154 ?? 15
229 f 12 115 f 10 41 ?? 3.0 164 f 13
230 f 11 140 f 14 43 ?? 1.5 164 f 8
214 f 179 f 55 f 123 zt
EENA
Before 9 12 2.1* IO*
240 f 140 * 43 * 169 zt
8 14 2.0 7.0
After
Before
234 f 4 169 f 14 51 ?? 2.0* 149 ?? 4.0;
246 f 136 f 46 * 172 f
After 15 15 4.0 13
205 f 9* 125 zt 10 45 ?? 4.0 145 f 8*
pPlus!minus values are mean f SEM for continuous variables. ?? P values are for comparisons among the three groups by analysis of variance. CEEMPA, conjugated equine estrogens and medroxy progesterone acetate; EENA, estradiol, estriol and norethisterone DCEE, conjugated equine estrogens and 10 days of ethinyl estradiol + desogestrel; ns, not significant.
The cumulative therapeutic response which was calculated in each group was compared with initial values following the adjustment period. Student’s t-test for paired data was used to evaluate the significance of intergroup
acetate;
differences, while Student’s t-test for unpaired data evaluated the intragroup differences. Blood was taken at the end of each cycle (Day 26-28 of the treatment cycle). Venous blood was collected in commercial
Cholesterol
Tri$ycerii
percent
p””
140
,140
_*.___._.- .~---+ ___--IW-
__.* - .
___---
_n--._.._.._
._,_._...---
*,1W
._.._.__ _----.---*
HDL-cholesterol petcent 140
7
??
IS0 -
* ,*__ ----
I20
I110
___a*--
_!‘tw
___---
*
)‘W
_J
A’
_....+.
._..-o---...
. ..__._.
110
_ /--..
____‘__A
fW
??
00 -_ 0
0
3
*
month -
EENA.... ‘..CEEYPA ’ CCEE
Fig. 1. The percent changes in blood lipoproteins
during
the 9-month
treatment
with DCEE, CEEMPA and EENA. Article
108
Taaknoret al.
EDTA tubes, after an overnight fast of 12 h. Plasma was separated by low speed centrifugation (1500 g x 15 mm). TC, TG and HDL-C measurements were performed within 6 h using Reflotron dry chemistry systems from Boehringer Mannheim, using cholesterol, triglyceride and HDL strips. LDL cholesterol was calculated using the Friedewald equation [ 121. Results The study population is presented in Table 1. The four groups did not differ in age, number of years in menopause, or body composition. The blood lipid profiles during the study periods are recorded in Table 2. The control group showed no change in lipid values during the 9 months. The relative effects of the three protocols on the trimonthly percentage changes from the baseline for each medication are compared in Fig. 1. All of the trends appear soon after the first trimonthly period. DCEE significantly increased HDL-C (30%) and lowered LDL-C (27%). The 12% reduction in TC was not statistically signifi-
Table 3. Changes in blood lipid ratios in the four groups, before and after the 9-month study period. TC/HDL
Control DCEE CEEMPA EENA
LDL/HDL
Before
After
Before
After
5.30 5.34 5.61 5.45
5.59 3.89**** 4.658 4.65
3.61 3.81 4.06 3.86
4.00 2.24**** 3.01* 3.07
Data represent mean of all the ratios. P values were computed after a paired r-test in each group and by a t-test between the groups. *Statistically significant in the same group, P c 0.05. ?? *Statisticahy significant as compared with the two other groups. TC, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; CEEMPA, conjugated equine estrogens and medroxy progesterone acetate; EENA, estradiol, estriol and norethisterone acetate; DCEE, conjugated equine estrogens and 10 days of ethinyl estradiol + desogestrel. Int J GynecolObstet39
cant, nor was there a significant change in TG. This trend remained evident throughout the 9 months. The TC/HDL ratio was reduced favorably, from 5.7 to 3.97 (-44%), while the LDL/I-IDL ratio improved from 4.07 to 2.27 (-79%) by the end of the ninth month of treatment (Table 3). CEEMPA significantly and continuously increased HDL-C (causing a rise of 20% from the initial value) while decreasing LDL-C 10%. There was no significant change in TC, but there was a non-significant trend towards elevation of TG. EENA significantly lowered TC and LDLC levels (9% and 15% respectively) without changing the TG or HDL-C levels (Fig. 1). The ratios of TC/HDL and LDWHDL were also statistically favorable in the DCEE group when compared with EENA and CEEMPA (Table 3). Discussion The DCEE group used a relatively new progestogen (desogestrel) which has a highly selective progestogenic effect and very low androgenicity [3,8,14]. The increased HDL-C and lowered LDL-C level, as well as the favorable TC/HDL and LDL/HDL ratios, corroborate the findings of Kloosterboer and Rekers [8] who found similar results among users of oral contraceptives containing desogestrel. The CEEMPA increase in HDL-C and the decrease in LDLC agrees with other studies [7,19]. In order to evaluate the estrogen bioequivalence and its effect on lipids as summarized by Upton [ 171 we could calculate an estrogenic load effect on lipids per cycle (total estrogen for the woman’s cycle in relative bioequivalent values of 0.625 mg premarin = PP = 5 pg ethinyl estradiol = 0.5 mg 17-/S estradiol). Thus, the DCEE estrogenic load affecting lipids is 100 PP per cycle (22 days x 4 PP + 6 days x 2 PP = 100 PP). The estrogenic load per cycle of CEEMPA = 25 PP. The estrogenic load per cycle of EENA = 75 PP (15 days x 1 PP + 10 days x 6 PP = 75 PP).
Effect of desogestrel for HRT
Therefore, the relative estrogenic load is as follows: EENA > DCEE > CEEMPA (100 PP > 75 PP > 25 PP). As seen in Fig. 1, there was no change in HDL in the EENA group, despite the highest estrogen load. This may be caused by the blunting effect of norethisterone acetate which has a strong androgenic effect. Our data corroborated previous studies [2,4,13] which suggested that medroxyprogesterone acetate has less of a deleterious effect on blood lipids than 19-nortestosterone derivatives. Thus, despite the lower estrogenic load of CEEMPA preparations, the HDL-C values increased significantly. HDL-C increased markedly and significantly in the DCEE group, as compared to the CEEMPA group and EENA group. This increase cannot be explained by the moderate estrogenic load of DCEE. It is likely that desogestrel contributes a great deal to this increase in HDL, when compared with either medroxyprogesterone or with norethisterone. Furthermore, our data agree with other reports [8,1 l] which showed an extraordinarily beneficial effect of desogestrel, together with a low intrinsic androgenicity, when compared with the second generation progestin used in oral contraceptives. In addition, the triglycerides did not change in the EENA group, but were increased in the CEEMPA and DCEE groups. There could be two reasons for this phenomenon: alkylated estrogens and equine estrogens in DCEE or CEEMPA protocols increase triglyceride and VLDL-C production more effectively than natural estrogens in the EENA preparation [20]. 19-Nortestosterone derivatives in EENA have a greater androgenic potential than medroxyprogesterone in CEEMPA. This fact effectively augmented the triglyceride removal by the liver, while inhibiting VLDL-C production. A rise was also noted in the TG values (+40%) among women treated with an oral contraceptive containing desogestrel [5,11]. The strongest LDL decrease was observed with DCEE. This may result from the com-
109
bined effect of estrogen load and from the beneficial effect of progestogen. Simons [15] also showed that the TC/HDLC ratio correlates with atherosclerotic heart disease in a manner similar to that of the LDL-C levels. Observations from our study show that in the DCEE group (Table 3) this atherogenic quotient was the lowest when compared with the initial quotient and with the data from the other preparations. This preliminary observation will require further confirmation from additional studies in order to decide which type of HRT to use. Summary The aim of the present study was to compare the blood lipid profile of healthy postmenopausal women with either one of the three protocols. Eighty-nine postmenopausal women attending the Jerusalem Climacteric Clinic Center were enrolled in this study. They were divided into four random groups: controls without HRT (24 women), DCEE treatment group (29 women), CEEMPA treatment group (23 women) and EENA treatment group (13 women). Blood lipid profiles of TC, LDL-C, HDL-C and TG were performed at the beginning of the study, again after a run-in period of lifestyle adjustment and again at 3-month intervals, for a period of 9 months. The DCEE-treated group showed a significant rise in HDL-C and a decrease in LDL-C starting after 3 months of treatment. The EENAtreated women showed a significant decrease in TC and LDL-C, when compared with their initial values, after only 9 months of treatment. However, no change was noted in HDL-C or TG. The CEEMPA group showed an increase in HDL-C values when compared with their initial values after 9 months, but no decrease in TC or LDL-C was shown after 9 months of treatment. The TG values of the DCEE and the CEEMPA groups tended to rise, when compared with the control and the EENA groups. Article
110
Tadmor et al.
Acknowledgments We would like to thank David Grossman for editing this paper.
12
References 13 1 American Heart Association: Dietary guidelines for healthy American adults: A statement for physicians and health professionals by the Nutrition Committee, American Heart Association. Circulation 74: 1465A, 1986. 2 Barnes RB, Roy S, Lobo RA: Comparison of lipid and androgen levels after conjugated estrogen or depomedroxyprogesterone acetate treatment in postmenopausal women. Obstet Gynecol 66: 216, 1985. 3 Cullberg G: Pharmacodynamic studies on desogestrel administered alone and in combination with ethinylestradiol. Acta Obstet Gynecol Stand Suppl. 133: 1, 1985. 4 Fahraeus L, Sydsjo A, Wallentin L: Lipoprotein changes during treatment of pelvic endometriosis with medroxyprogesterone acetate. Fertil Steril 45: 503, 1986. 5 Harvengt C, Desager JP, Gaspard U, Lepot M: Changes in lipoprotein composition in women receiving two lowdose oral contraceptives containing ethinylestradiol and gestodene progestins. Contraception 37 (6): 565, 1988. 6 Jensen J, Christiansen C: Dose response effect on serum lipids and lipoproteins following combined oestrogenprogestogen therapy in post menopausal women. Maturitas 9: 259, 1987. 7 Kable WT, Gallagher JC, Nachtigall L, Goldgar D: Lipid changes after hormone replacement therapy for menopause. J Reprod Med 35 (5): 512, 1990. 8 Kloosterboer I-U, Rekers H: Effects of three combined oral contraceptive preparations containing desogestrel plus ethinyl estradiol on lipid metabolism in comparison with two levonorgestrel preparations. Am J Obstet Gynecol 163: 370, 1990. 9 Knopp RH: The effects of postmenopausal estrogen therapy on the incidence of arteriosclerotic vascular disease. Obstet Gynecol 72 (5 Suppl): 23S, 1988. 10 La-risa JC: The varying effects of progestins on lipid levels and cardiovascular diseases. Am J Obstet Gynecol 158: 1621, 1988. 11 Leuven JS, de Pagter HA, Dersjant-Roorda MA, Helmerhorst FA, Roelofsen J: Effect of two monophasic
Int J Gynecol Obstet 39
14
15
16
17
18
19
20
oral contraceptives containing gestodene or desogestrel on serum lipoprotein lipid levels. Int J Fertil 34 (Suppl): 55, 1989. National cholesterol education program expert panel on detection, evaluation and treatment of high blood cholesterol in adults: Report. Arch Intern Med 148: 36, 1988. Ottosson UB, Johansson BG, Von Schoults B: Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogen and natural progesterone. Am J Obstet Gynecol 151: 746, 1985. Rubeck Petersen K, Skouby SO, Dreisler A, Kuhl C, Svenstrup B: Comparative trial of the effects on glucose tolerance and lipoprotein metabolism of two new oral contraceptives containing gestoden and desogestrel. Acta Obstet Gynecol Stand 67 (I): 37, 1988. Simons LA: Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries. Am J Cardiol 57: 5G, 1986. Tikkanen MJ, Kuusi T, Mikkila EA, Sipinnen S: Post menopausal hormone replacement therapy: Effect of progestogen on serum lipids and lipoproteins. Maturitas 8: 7, 1986. Upton, G. Virginia: Contraception for the perimenopausal patient. In: Obstetrics and Gynecological Clinics: The Menopause. p 207, 1988. Vejtrop M, Christiansen MS, Vejtrop L, Larsen JF: Serum lipoproteins changes in climacteric women induced by sequential therapy with natural estrogens and medroxyprogestrone Acetate. Acta Obstet Gynecol Stand 65: 391, 1986. Wallace RB, Anderson RA: Blood lipids, lipid-related mensures and the risk of atherosclerotic cardiovascular disease. Epidemiol Rev 9: 95, 1987. Windler, E, Kovanen, PT, Chao YS, Brown MS, Have1 R, Goldstein JL: The estradiol-stimulated lipoprotein receptor of rat liver. J Biol Chem 255: 10464, 1980.
Address for reprhrtsr
O.P. Tndmor Departmentof Gynecology Shaare Zedek MedIeal Center P.O. Box 3w Jemsalem, Israel
Int J Gynecol Obstet, 1992, 39: 105-110 International Federation of Gynecology and Obstetrics
The effect of desogestrel for hormone replacement therapy on the blood lipid profiles of postmenopausal women O.P. Tadmora,
Y. Kleinmanb,
aDepartment of Gynecology, ‘Gastroenterology
R. Goldsteinc
Shaare Zedek Medical Center, bMetabolic
Laboratory.
and Y.Z. Diamanta Unit, Department of Internal Medicine. Bikur Cholim Hospital,
Shaare Zedek Medical Center, Jerusalem
(Israel)
(Received December 22nd, 1991) (Revised and accepted March 18th, 1992)
Abstract
Objective: To determine the effect of a hormone replacement protocol containing conjugated equine estrogens and desogestrel (which has a highly selective progestogenic and low androgenic effect) as the progestogen, on the plasma lipid profile, as compared with two other hormone replacement treatments (HRT). Method: Eighty-nine healthy postmenopausal women were divided prospectively into four groups. A control group of 24 women did not receive HRT. Twenty-nine women received conjugated equine estrogen and medroxyprogesterone, and 13 women received a protocol containing estradiol, estriol and norethisterone acetate. Fasting blood lipid was taken at the end of each third cycle. The cumulative therapeutic response was calculated in each group as compared with initial values and between groups. Significance was analyzed by t-tests. Results: A protocol containing desogestrel significantly decreased low-density lipoprotein cholesterol (27%; P < 0.05) and increased high-density lipoprotein cholesterol (HDL-C) by 30% (P < 0.05%) after 9 months. The ratio of total cholesterol to HDLC also decreased significantly (44%; P < 0.05). Conclusion: The most beneficial effect on plasma lipid profile was obtained with an HRT protocol containing desogestrel as the progesterone.
0020-7292/92l~O5.00 0 1992 International
Federation of Gynecology and Obstetrics Printed and Published in Ireland
Keywords: Hormone replacement therapy; Lipoproteins; Desogestrel; Menopause; Cholesterol; High density lipoproteins. Introduction
Estrogen replacement therapy has been shown to reduce low density lipoprotein cholesterol (LDL-C), while increasing high density lipoprotein cholesterol (HDL-C) [9]. However, most progestins increase LDL-C levels and lower HDL-C levels [ 16,181. However, common hormone replacement therapy (HRT) involves cyclical adjustments of estrogen and progestogen because of the increased risk of endometrial carcinoma. There is therefore great concern whether progestogens may offset or neutralize the beneficial effect of estrogen [6]. The body of data presented in the literature is controversial. In many reports progestogen supplementation did not blunt the estrogen LDL-C lowering effect, whereas some progestin products decreased HDL-C to lower than the pretreatment level [ 10,181. Desogesterol, a relatively new progestin, belongs to the third generation of oral contraceptives. It has been shown to have a high relative binding affinity to human progesterone receptors, but a low affinity to human androgen receptors. Desogestrel has been reported to have a Article
106
Tadmor et al.
lipid-beneficial effect, especially on the elevation of APO-AI and HDL2. We have found no studies which compared the efficacy of combinations containing desogestrel among postmenopausal women. Taking advantage of this effect on lowering lipids, we examined the influence of a novel protocol for HRT containing desogestrel on the lipid profile of postmenopausal women. Materials and methods postmenopausal Eighty-nine healthy women attending the Jerusalem Municipal Climacteric Center Clinic and the Shaare Zedek Climacteric Clinic were enrolled in the study. All women had undergone natural or surgical menopause within the last 5 years. Patients were divided into four groups: a control group (24 women who did not receive HRT), a DCEE group which was given conjugated equine estrogens for 15 days and an ethinyl estradiol-desogestrel combination for the next 10 days, as found in the contraceptive pill (29 women); a CEEMPA group, which was given a fixed protocol of conjugated equine estrogens and medroxyprogesterone acetate, marketed under the trade name Premaril Plus (23 women); and an EENA group, which was given a fixed regimen of estradiol, estriol and norethisterone acetate, marketed under the trade name Trisequens (13 women). All of the women had a 1-month
Table 1.
adjustment period, in order to provide and institute the recommended dietary guidelines for the healthy population suggested by the Nutrition Committee of the American Heart Association [ 11. Treatment with HRT was begun after this period. The DCEE group took conjugated equine estrogen (0.625 mg/day) for 15 days and ethinyl estradiol 30 pg together with desogestrel 150 pg for the next 10 days. The EENA group was treated for 28 days per month with a fixed combination of estradiol, estriol and norethisterone acetate, according to the printed dosage: 12 days of estradiol 2 mg and estriol 1 mg; 10 days of estradiol 2 mg, estriol 1 mg and norethisterone acetate 1 mg; and 6 days of estradiol 1 mg and estriol 0.5 mg. The CEEMPA group was treated for 25 days with conjugated equine estrogens 0.625 mg. Medroxyprogesterone acetate 5 mg was added from Day 13 to Day 25. Study medications were offered free of charge and patients were examined every 3 months for adverse effects. Compliance to therapy was checked by pill counting. The control group was monitored in the clinic, but the women did not receive HRT. The blood lipids profile (total cholesterol TC, LDL-C, HDL-C and triglycerides TG) was determined at the beginning of the study, after 1 month of lifestyle adjustment, and at 3-month intervals, for g-months.
Physical characteristics of the subjects in the three groupsa.
Characteristics
DCEE (n = 29)
Age (years) Weight (kg) Height (cm) Body Mass Index (kp/m*) Menopause period (years)
54 f 66.9 zt 160.8 zt 25.4 zt 3*
1.5 5.1 4.5 2.9 0.7
CEEMPA (n = 23)
EENA (n = 13)
56 ZIZ1 66.4 zt 6.3 161.3 zt 3.1 25.5 zt 2.6 5 * 1.0
53 f 67.5 zt 161.9 f 25.8 f 3f
Control (n = 24) 1 7.5 6.5 2.7 1.0
53 * 65.9 zt 160.9 f 25.4 f 4+0
P value*
1 10.4 6.9 2.8
ns ns ns ns ns
aPlus/minus values are mean * SEM for continuous variables. *P values are for comparisons among the three groups by analysis of variance. CEEMPA, conjugated equine estrogens and medroxy progesterone acetate; EENA, estradiol, estriol and norethisterone acetate; DCEE, conjugated equine estrogens and 10 days of ethinyl estradiol+ desogestrel; ns, not significant. Int J Gynecol Obstet 39
Effect of desogestrelfor HRT
Table 2.
101
Changes in blood lipids in the three groups before and after 9 monthsa. Control
TC TG HDL-C LDL-C
CEEMPA
DCEE
Before
After
Before
After
224 f 14 136 f 12 42 f 2.0 154 ?? 15
229 f 12 115 f 10 41 ?? 3.0 164 f 13
230 f 11 140 f 14 43 ?? 1.5 164 f 8
214 f 179 f 55 f 123 zt
EENA
Before 9 12 2.1* IO*
240 f 140 * 43 * 169 zt
8 14 2.0 7.0
After
Before
234 f 4 169 f 14 51 ?? 2.0* 149 ?? 4.0;
246 f 136 f 46 * 172 f
After 15 15 4.0 13
205 f 9* 125 zt 10 45 ?? 4.0 145 f 8*
pPlus!minus values are mean f SEM for continuous variables. ?? P values are for comparisons among the three groups by analysis of variance. CEEMPA, conjugated equine estrogens and medroxy progesterone acetate; EENA, estradiol, estriol and norethisterone DCEE, conjugated equine estrogens and 10 days of ethinyl estradiol + desogestrel; ns, not significant.
The cumulative therapeutic response which was calculated in each group was compared with initial values following the adjustment period. Student’s t-test for paired data was used to evaluate the significance of intergroup
acetate;
differences, while Student’s t-test for unpaired data evaluated the intragroup differences. Blood was taken at the end of each cycle (Day 26-28 of the treatment cycle). Venous blood was collected in commercial
Cholesterol
Tri$ycerii
percent
p””
140
,140
_*.___._.- .~---+ ___--IW-
__.* - .
___---
_n--._.._.._
._,_._...---
*,1W
._.._.__ _----.---*
HDL-cholesterol petcent 140
7
??
IS0 -
* ,*__ ----
I20
I110
___a*--
_!‘tw
___---
*
)‘W
_J
A’
_....+.
._..-o---...
. ..__._.
110
_ /--..
____‘__A
fW
??
00 -_ 0
0
3
*
month -
EENA.... ‘..CEEYPA ’ CCEE
Fig. 1. The percent changes in blood lipoproteins
during
the 9-month
treatment
with DCEE, CEEMPA and EENA. Article
108
Taaknoret al.
EDTA tubes, after an overnight fast of 12 h. Plasma was separated by low speed centrifugation (1500 g x 15 mm). TC, TG and HDL-C measurements were performed within 6 h using Reflotron dry chemistry systems from Boehringer Mannheim, using cholesterol, triglyceride and HDL strips. LDL cholesterol was calculated using the Friedewald equation [ 121. Results The study population is presented in Table 1. The four groups did not differ in age, number of years in menopause, or body composition. The blood lipid profiles during the study periods are recorded in Table 2. The control group showed no change in lipid values during the 9 months. The relative effects of the three protocols on the trimonthly percentage changes from the baseline for each medication are compared in Fig. 1. All of the trends appear soon after the first trimonthly period. DCEE significantly increased HDL-C (30%) and lowered LDL-C (27%). The 12% reduction in TC was not statistically signifi-
Table 3. Changes in blood lipid ratios in the four groups, before and after the 9-month study period. TC/HDL
Control DCEE CEEMPA EENA
LDL/HDL
Before
After
Before
After
5.30 5.34 5.61 5.45
5.59 3.89**** 4.658 4.65
3.61 3.81 4.06 3.86
4.00 2.24**** 3.01* 3.07
Data represent mean of all the ratios. P values were computed after a paired r-test in each group and by a t-test between the groups. *Statistically significant in the same group, P c 0.05. ?? *Statisticahy significant as compared with the two other groups. TC, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; CEEMPA, conjugated equine estrogens and medroxy progesterone acetate; EENA, estradiol, estriol and norethisterone acetate; DCEE, conjugated equine estrogens and 10 days of ethinyl estradiol + desogestrel. Int J GynecolObstet39
cant, nor was there a significant change in TG. This trend remained evident throughout the 9 months. The TC/HDL ratio was reduced favorably, from 5.7 to 3.97 (-44%), while the LDL/I-IDL ratio improved from 4.07 to 2.27 (-79%) by the end of the ninth month of treatment (Table 3). CEEMPA significantly and continuously increased HDL-C (causing a rise of 20% from the initial value) while decreasing LDL-C 10%. There was no significant change in TC, but there was a non-significant trend towards elevation of TG. EENA significantly lowered TC and LDLC levels (9% and 15% respectively) without changing the TG or HDL-C levels (Fig. 1). The ratios of TC/HDL and LDWHDL were also statistically favorable in the DCEE group when compared with EENA and CEEMPA (Table 3). Discussion The DCEE group used a relatively new progestogen (desogestrel) which has a highly selective progestogenic effect and very low androgenicity [3,8,14]. The increased HDL-C and lowered LDL-C level, as well as the favorable TC/HDL and LDL/HDL ratios, corroborate the findings of Kloosterboer and Rekers [8] who found similar results among users of oral contraceptives containing desogestrel. The CEEMPA increase in HDL-C and the decrease in LDLC agrees with other studies [7,19]. In order to evaluate the estrogen bioequivalence and its effect on lipids as summarized by Upton [ 171 we could calculate an estrogenic load effect on lipids per cycle (total estrogen for the woman’s cycle in relative bioequivalent values of 0.625 mg premarin = PP = 5 pg ethinyl estradiol = 0.5 mg 17-/S estradiol). Thus, the DCEE estrogenic load affecting lipids is 100 PP per cycle (22 days x 4 PP + 6 days x 2 PP = 100 PP). The estrogenic load per cycle of CEEMPA = 25 PP. The estrogenic load per cycle of EENA = 75 PP (15 days x 1 PP + 10 days x 6 PP = 75 PP).
Effect of desogestrel for HRT
Therefore, the relative estrogenic load is as follows: EENA > DCEE > CEEMPA (100 PP > 75 PP > 25 PP). As seen in Fig. 1, there was no change in HDL in the EENA group, despite the highest estrogen load. This may be caused by the blunting effect of norethisterone acetate which has a strong androgenic effect. Our data corroborated previous studies [2,4,13] which suggested that medroxyprogesterone acetate has less of a deleterious effect on blood lipids than 19-nortestosterone derivatives. Thus, despite the lower estrogenic load of CEEMPA preparations, the HDL-C values increased significantly. HDL-C increased markedly and significantly in the DCEE group, as compared to the CEEMPA group and EENA group. This increase cannot be explained by the moderate estrogenic load of DCEE. It is likely that desogestrel contributes a great deal to this increase in HDL, when compared with either medroxyprogesterone or with norethisterone. Furthermore, our data agree with other reports [8,1 l] which showed an extraordinarily beneficial effect of desogestrel, together with a low intrinsic androgenicity, when compared with the second generation progestin used in oral contraceptives. In addition, the triglycerides did not change in the EENA group, but were increased in the CEEMPA and DCEE groups. There could be two reasons for this phenomenon: alkylated estrogens and equine estrogens in DCEE or CEEMPA protocols increase triglyceride and VLDL-C production more effectively than natural estrogens in the EENA preparation [20]. 19-Nortestosterone derivatives in EENA have a greater androgenic potential than medroxyprogesterone in CEEMPA. This fact effectively augmented the triglyceride removal by the liver, while inhibiting VLDL-C production. A rise was also noted in the TG values (+40%) among women treated with an oral contraceptive containing desogestrel [5,11]. The strongest LDL decrease was observed with DCEE. This may result from the com-
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bined effect of estrogen load and from the beneficial effect of progestogen. Simons [15] also showed that the TC/HDLC ratio correlates with atherosclerotic heart disease in a manner similar to that of the LDL-C levels. Observations from our study show that in the DCEE group (Table 3) this atherogenic quotient was the lowest when compared with the initial quotient and with the data from the other preparations. This preliminary observation will require further confirmation from additional studies in order to decide which type of HRT to use. Summary The aim of the present study was to compare the blood lipid profile of healthy postmenopausal women with either one of the three protocols. Eighty-nine postmenopausal women attending the Jerusalem Climacteric Clinic Center were enrolled in this study. They were divided into four random groups: controls without HRT (24 women), DCEE treatment group (29 women), CEEMPA treatment group (23 women) and EENA treatment group (13 women). Blood lipid profiles of TC, LDL-C, HDL-C and TG were performed at the beginning of the study, again after a run-in period of lifestyle adjustment and again at 3-month intervals, for a period of 9 months. The DCEE-treated group showed a significant rise in HDL-C and a decrease in LDL-C starting after 3 months of treatment. The EENAtreated women showed a significant decrease in TC and LDL-C, when compared with their initial values, after only 9 months of treatment. However, no change was noted in HDL-C or TG. The CEEMPA group showed an increase in HDL-C values when compared with their initial values after 9 months, but no decrease in TC or LDL-C was shown after 9 months of treatment. The TG values of the DCEE and the CEEMPA groups tended to rise, when compared with the control and the EENA groups. Article
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Acknowledgments We would like to thank David Grossman for editing this paper.
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Address for reprhrtsr
O.P. Tndmor Departmentof Gynecology Shaare Zedek MedIeal Center P.O. Box 3w Jemsalem, Israel
