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Hypercholesterolemia in postmenopausal women: Metabolic defects and response to low-dose lovastatin
Citations from the Literature / Int. J. Gynecol. Obstet. 47 (1994) 83-91 Department of IVF of the Rotterdam Academic Hospital. Patients: One hundred forty-five patients with patent tubes entered the IVF program. Main Outcome Measure: Pregnancy rates in both groups and ultrasound (US) assessment during fallopian cannulation and ET. Results: Transvaginal cannulation of the tube appears not to be sufficiently accurate when performed without US guidance. Catheter damage occurred in many cases. The previously reported superior implantation rate after intrafallopian transfer in comparison with intrauterine transfer could not be confirmed. Conclusions: Intrauterine transfer of cleaved embryos remains the method of choice in IVF.
GYNECOLOGICAL ENDOCRINOLOGY Relative risks and benefits of lowterm estrogen replacement therapy: A decision aaalysis Gorsky R.D.; Koplan J.P.; Peterson H.B.; Thacker S.B. USA OBSTET GYNECOL 1994 83/2 (161-166) Objective: To evaluate the relative risks and benefits of exogenous estrogen use among women entering the climacteric and to consider estrogen use for relief of symptoms or preventir\n nf&a-!ar.a MPtkAA.. _,O."‘. nn,.;.;rmU.m.,JYh, snnl.r.i. w9.2 orrPrr .1"1S "S Y."".."". ‘.."bI*\N.a. "YY ,,nmi .. . tfl L" UllYY the value of estrogen replacement therapy in a hypothetical cohort of 10 000 women assumed to be. age 50 years; health outcomes were extrapolated to age 75. Risk ratios for mortality and morbidity of health outcomes associated with the use of estrogen replacement therapy were based on longitudinal studies reported in the literature. Results: Estrogen use for 25 years would decrease fatal coronary heart disease events by 48% (567 cases), decrease deaths from hip fracture by 49% (75), increase deaths from breast cancer by 21% (39), and increase deaths from endometriai cancer by 207% (29 excess deaths). Gn baiante, 25 years of estrogen replacement therapy in a cohort of 10000 women would prevent 574 deaths. Further, women using estrogens for 25 years would gain 3951 quality-adjusted life years compared with women not using estrogens. Sensitivity analysis suggests that the benefits of estrogen replacement therapy outweigh the risks under most assumptions. Conclu&.n.. rn n k.r~,.tL~t;ml -,.~.lnt;nn-,.~narl snslrm;. tl.n hm..lth YI”I,a. I88 &aII,p”,C”ML, ppA,arw~r”~rr” nlunn,U1Y, ,.n.. 11”YXLfifi benefits of postmenopausal estrogen replacement exceed the health risks incurred. Nevertheless, clinicians must still evaluate each individual’s risks and needs. Effect of coathms combiaed estrogen aad desogestrel hormone @acmeat therapy on serum lipids and lipoproteins Marsh M.S.; Crook D.; Whitcroft S.I.J.; Worthington M.; Whitehead M.I.; Stevenson J.C. GBR OBSTET GYNECOL 1994 83/I (19-23) Objective: To determine the effects of continuous combined hormone replacement therapy with desogestrel and 17-estradiol (E2) on serum lipids and lipoproteins. Methods: Fifty-seven healthy postmenopausal women of less than 60 years of age
87
were studied prospectively and treated with oral desogestrel 0.15 mg/day and micronized 17j3-E21 mg/day, both taken continuously. Fasting venous blood samples for serum lipids and lipoproteins were taken before and after 6 and 12 months of treatment. Results: Thirty-two women completed the study. Levels of all serum lipids and lipoproteins fell significantly by 6 months and remained low at 12 months. The mean percentage reduction after 12 months of treatment was 12.8% for highdensity lipoprotein (HDL) cholesterol, which largely resulted from a reduction in the HDLz subfraction, which fell by 25.7%. The mean percentage reduction for both low-density lipoprotein (LDL) cholesterol and triglycerides was 7.7%. The median percentage reduction for lipoprotein (a) was 17.6%. Conclusions: This combination of hormone replacement therapy had profound effects on serum lipids and lipoproteins. According to current concepts, reductions in total and LDL cholesterol, triglycerides, and lipoprotein (a) may reduce cardiovascular disease risk. The reduction in HDL was unexpected, given the rise in HDL that has been demonstrated when desogestrel is combined with ethinyl estradiol in the contraceptive pill. The lowering of HDL observed in this study is undesirable and may be potentially harmful. Our results indicate that when desogestrel 0.15 mg/day is combined with micronized 17-E2 1 mg/day in a continuous manner, the effects of the progestogen on HDL predominate and cause a reduction in HDL and the HDLz subfraction. Hype4&&mhia ia postmeaopaasal women: Metabolic defects aad respome to Iowdose lovastatia Arca M.; Vega G.L.; Grundy S.M. USA J AM MED ASSOC 1994 271/6 (453-459) Objective: To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to detennine whether a low dose of lovastatin will correct this ab*._ normauty. Design: in the first part of the study, tiiriiover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placebocontrolled, randomized, double-blind study using lovastatin as the therapeutic agent. Setting: The General Clinical Research Center of the University of Texas Southwestern Medical rpnt*r lbllc4c IltiliTino f2rilities 2nd __...“., __..““, __.__ -_.P innatipnt ...= __._... anfl _.._ nlltnstit?nt ___r_______ _________“, ____ the Veterans Affairs Medical Center, Dallas, TX. Patients: For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean f S.D. LDL cholesterol, 4.78 f 0.59 mmol/l [I85 & 23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean * S.D. LDL cholesterol, 3.31 * 0.39 mmolfl [I28 f 15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study. Interventions: In the drug study, patients received blindly both r.n_._,>\ -_> placeoo. _,___L_.*_:_ ,,_^^.._^^. ,_ lovastatm (1” mua, ana ham A...____ VUL~UIIIC: I*ICIJUL=D. 111 the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy. Results: In the LDL turnover study, mean ( ?? S.D.) input (production) rates for LDL apolipoprotein B (apo B)
88
Citations from the Literature/ Int. J. Gynecol. Obstet. 47 (1994) 83-91
were similar for hypercholesterolemic women and control women (12.4 [*3.2] mg/kg per day and 11.1 [*2.2] mgkg per day, respectively). In contrast, mean (*SD.) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [ +0.04] pools per day) were significantly lower than those in normolipidemic women (0.35 [ ~0.031 pools per day). In the drug trial, lovastatin therapy reduced mean ( f SD.) total cholesterol and LDL cholesterol from 7.03 ( f 1.16) mmol/L (272 [a451 mg/dL) and 4.42 (~0.80) mmol/L (171 [*31] mg/dL), respectively, to 5.70 (f 1.03) mmol/L (221 [*40] mg/dL) and 3.46 (kO.85) mmovl (134 [ ~331 mg/dL). Conclusions: The turnover data suggest that hypercholesterolemia in postmenopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause. Changes in collagen compositionaad cross-liis in bone aod skin of osteopovoticpostmenopaosalwomen treated with percutaneous estradiol implsats Nigel Holland E.F.; Studd J.W.W.; Mansell J.P.; Leather A.T.; Bailey A.J.
conjugated equine estrogen before and after progestin administration. Methods: We randomized 103 postmenopausal women into a control group and into two groups receiving either 0.625 mg or 1.25 mg of conjugated equine estrogen for 4 months and then the same estrogen dose plus cyclic medroxyprogesterone acetate for 8 months. Results: Both estrogen doses similarly lowered (P < 0.01) low-density lipoprotein (LDL) cholesterol and raised (P < 0.01) high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, triglyceride levels of all lipoproteins, and sex hormone-binding globulin capacity. Cyclic addition of the progestin reduced HDL cholesterol (P < 0.01) and apolipoprotein A-l (P c 0.05), but not LDL cholesterol in either estrogen group. A greater lowering of HDL cholesterol (P c 0.05) in response to the progestin was seen with the 0.625-mg dose of estrogen. Estrogen-induced triglyceride enrichment of HDL and LDL was not reversed by the progestin. Conclusions: The only significant quantitative difference in lipoprotein levels between the doses of conjugated equine estrogen before or after administration of medroxyprogesterone acetate was a greater decline in HDL cholesterol levels with the lower dose after 4 months of the progestin. This difference was not sustained over time. There were no differences between doses in the estrogeninduced triglyceride enrichment of lipoproteins, and these qualitative changes were not affected by the progestin.
GBR
OBSTET GYNECOL 1994 83/2 (180-183) Objective: To determine the effects of percutaneous estradiol(E2) implants on the collagen composition and maturity in the bone and skin of osteoporotic postmenopausal women. Methods: Sixteen postmenopausal women with low bone mineral density were treated for I year with 75mg E2 implants. Iliac crest bone and skin biopsies were analyzed for collagen content and collagen cross-links before treatment and at 1 year. Dual energy X-ray absorptiometry of the lumbar spine and proximal femur was also performed before and after 1 year of therapy. Results: The cortical bone showed a significant increase in the mature cross-links of both hydroxylysylpyridinoline (P < 0.01) and lysylpyridinoline (P < O.Ol), with a significant reduction in the percentage of collagen (P < 0.001). The pattern was similar in trabecular bone, with lysylpyridinoline increasing significantly (P c 0.05). The skin exhibited a significant reduction in the immature cross-link hydroxylysinonorleucine (P < O.Ol), but no signiticant change in the percentage of collagen content or the mature cross-link histidinohydroxylysinonorleucin. The median increases in bone density were 11.5% at the spine and 4.34% at the total hip. The median post-treatment serum E2 level was 639 pmoVL. Quantitative aod qualitative ckanges io lipids, lipoproteins, apolipoproteiaA-I, sod sex hormone-bindingglobulin doe to two doses of coo-ted equine estrogen with and without a progestin Miller V.T.; Muesing R.A.; LaRosa J.C.; Stoy D.B.; Fowler SE.; Stillman R.J. USA OBSTET GYNECOL 1994 8312 (173-179) Objective: To determine whether the quantitative and qualitative effects on lipoproteins differ between two doses of
The iadepeodent effects of exercise sod estrogen on lipids and lipoproteinsin postmenopausalwomen Lindheim S.R.; Notelovitz M.; Feldman E.B.; Larsen S.; Khan F.Y. USA
OBSTET GYNECOL 1994 83/2 (167-172) Objective: To assess the effects of a moderate exercise program with and without oral estrogen replacement on levels of lipids and lipoproteins in postmenopausal women. Methods: One hundred one postmenopausal women were randomized into four groups: control or sedentary (A’= 20), exercise alone (N= 25), estrogen replacement using 0.625 mg conjugated equine estrogen (N = 28), and exercise supplemented with conjugated equine estrogen (N = 28). The exercise groups were placed on a moderate exercise program. Following baseline testing, each group returned at 3 and 6 months for cardiorespiratory fitness testing and serum lipid and lipoprotein profiles. Results: We found a significant decrease in systolic blood pressure (P < 0.05) in all treatment groups. The maximum oxygen uptake increased by 9.0 and 7.8% in the exercise and conjugated equine estrogen/exercise groups, respectively, compared to the other groups (P < 0.05). These responses were seen at both 3 and 6 months. Total exercise time (time spent on the treadmill until exhaustion during testing) significantly increased in the exercise group by 21% (P < 0.01). Exercise alone was associated with significant decreases in total cholesterol (5.2%, P c 0.05), triglycerides (2%, P < 0.05), and low-density lipoprotein (LDL) cholesterol (10%. P < O.Ol), and a significant increase in the high-density lipoprotein (HDL) cholesterol-LDL ratio (17.2%, P < 0.01). Significant changes were noted in these values, as well as increases in HDL cholesterol (16 and 14.8%; P < 0.01) and apolipoprotein At (25.6
GYNECOLOGICAL ENDOCRINOLOGY Relative risks and benefits of lowterm estrogen replacement therapy: A decision aaalysis Gorsky R.D.; Koplan J.P.; Peterson H.B.; Thacker S.B. USA OBSTET GYNECOL 1994 83/2 (161-166) Objective: To evaluate the relative risks and benefits of exogenous estrogen use among women entering the climacteric and to consider estrogen use for relief of symptoms or preventir\n nf&a-!ar.a MPtkAA.. _,O."‘. nn,.;.;rmU.m.,JYh, snnl.r.i. w9.2 orrPrr .1"1S "S Y."".."". ‘.."bI*\N.a. "YY ,,nmi .. . tfl L" UllYY the value of estrogen replacement therapy in a hypothetical cohort of 10 000 women assumed to be. age 50 years; health outcomes were extrapolated to age 75. Risk ratios for mortality and morbidity of health outcomes associated with the use of estrogen replacement therapy were based on longitudinal studies reported in the literature. Results: Estrogen use for 25 years would decrease fatal coronary heart disease events by 48% (567 cases), decrease deaths from hip fracture by 49% (75), increase deaths from breast cancer by 21% (39), and increase deaths from endometriai cancer by 207% (29 excess deaths). Gn baiante, 25 years of estrogen replacement therapy in a cohort of 10000 women would prevent 574 deaths. Further, women using estrogens for 25 years would gain 3951 quality-adjusted life years compared with women not using estrogens. Sensitivity analysis suggests that the benefits of estrogen replacement therapy outweigh the risks under most assumptions. Conclu&.n.. rn n k.r~,.tL~t;ml -,.~.lnt;nn-,.~narl snslrm;. tl.n hm..lth YI”I,a. I88 &aII,p”,C”ML, ppA,arw~r”~rr” nlunn,U1Y, ,.n.. 11”YXLfifi benefits of postmenopausal estrogen replacement exceed the health risks incurred. Nevertheless, clinicians must still evaluate each individual’s risks and needs. Effect of coathms combiaed estrogen aad desogestrel hormone @acmeat therapy on serum lipids and lipoproteins Marsh M.S.; Crook D.; Whitcroft S.I.J.; Worthington M.; Whitehead M.I.; Stevenson J.C. GBR OBSTET GYNECOL 1994 83/I (19-23) Objective: To determine the effects of continuous combined hormone replacement therapy with desogestrel and 17-estradiol (E2) on serum lipids and lipoproteins. Methods: Fifty-seven healthy postmenopausal women of less than 60 years of age
87
were studied prospectively and treated with oral desogestrel 0.15 mg/day and micronized 17j3-E21 mg/day, both taken continuously. Fasting venous blood samples for serum lipids and lipoproteins were taken before and after 6 and 12 months of treatment. Results: Thirty-two women completed the study. Levels of all serum lipids and lipoproteins fell significantly by 6 months and remained low at 12 months. The mean percentage reduction after 12 months of treatment was 12.8% for highdensity lipoprotein (HDL) cholesterol, which largely resulted from a reduction in the HDLz subfraction, which fell by 25.7%. The mean percentage reduction for both low-density lipoprotein (LDL) cholesterol and triglycerides was 7.7%. The median percentage reduction for lipoprotein (a) was 17.6%. Conclusions: This combination of hormone replacement therapy had profound effects on serum lipids and lipoproteins. According to current concepts, reductions in total and LDL cholesterol, triglycerides, and lipoprotein (a) may reduce cardiovascular disease risk. The reduction in HDL was unexpected, given the rise in HDL that has been demonstrated when desogestrel is combined with ethinyl estradiol in the contraceptive pill. The lowering of HDL observed in this study is undesirable and may be potentially harmful. Our results indicate that when desogestrel 0.15 mg/day is combined with micronized 17-E2 1 mg/day in a continuous manner, the effects of the progestogen on HDL predominate and cause a reduction in HDL and the HDLz subfraction. Hype4&&mhia ia postmeaopaasal women: Metabolic defects aad respome to Iowdose lovastatia Arca M.; Vega G.L.; Grundy S.M. USA J AM MED ASSOC 1994 271/6 (453-459) Objective: To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to detennine whether a low dose of lovastatin will correct this ab*._ normauty. Design: in the first part of the study, tiiriiover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placebocontrolled, randomized, double-blind study using lovastatin as the therapeutic agent. Setting: The General Clinical Research Center of the University of Texas Southwestern Medical rpnt*r lbllc4c IltiliTino f2rilities 2nd __...“., __..““, __.__ -_.P innatipnt ...= __._... anfl _.._ nlltnstit?nt ___r_______ _________“, ____ the Veterans Affairs Medical Center, Dallas, TX. Patients: For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean f S.D. LDL cholesterol, 4.78 f 0.59 mmol/l [I85 & 23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean * S.D. LDL cholesterol, 3.31 * 0.39 mmolfl [I28 f 15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study. Interventions: In the drug study, patients received blindly both r.n_._,>\ -_> placeoo. _,___L_.*_:_ ,,_^^.._^^. ,_ lovastatm (1” mua, ana ham A...____ VUL~UIIIC: I*ICIJUL=D. 111 the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy. Results: In the LDL turnover study, mean ( ?? S.D.) input (production) rates for LDL apolipoprotein B (apo B)
88
Citations from the Literature/ Int. J. Gynecol. Obstet. 47 (1994) 83-91
were similar for hypercholesterolemic women and control women (12.4 [*3.2] mg/kg per day and 11.1 [*2.2] mgkg per day, respectively). In contrast, mean (*SD.) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [ +0.04] pools per day) were significantly lower than those in normolipidemic women (0.35 [ ~0.031 pools per day). In the drug trial, lovastatin therapy reduced mean ( f SD.) total cholesterol and LDL cholesterol from 7.03 ( f 1.16) mmol/L (272 [a451 mg/dL) and 4.42 (~0.80) mmol/L (171 [*31] mg/dL), respectively, to 5.70 (f 1.03) mmol/L (221 [*40] mg/dL) and 3.46 (kO.85) mmovl (134 [ ~331 mg/dL). Conclusions: The turnover data suggest that hypercholesterolemia in postmenopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause. Changes in collagen compositionaad cross-liis in bone aod skin of osteopovoticpostmenopaosalwomen treated with percutaneous estradiol implsats Nigel Holland E.F.; Studd J.W.W.; Mansell J.P.; Leather A.T.; Bailey A.J.
conjugated equine estrogen before and after progestin administration. Methods: We randomized 103 postmenopausal women into a control group and into two groups receiving either 0.625 mg or 1.25 mg of conjugated equine estrogen for 4 months and then the same estrogen dose plus cyclic medroxyprogesterone acetate for 8 months. Results: Both estrogen doses similarly lowered (P < 0.01) low-density lipoprotein (LDL) cholesterol and raised (P < 0.01) high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, triglyceride levels of all lipoproteins, and sex hormone-binding globulin capacity. Cyclic addition of the progestin reduced HDL cholesterol (P < 0.01) and apolipoprotein A-l (P c 0.05), but not LDL cholesterol in either estrogen group. A greater lowering of HDL cholesterol (P c 0.05) in response to the progestin was seen with the 0.625-mg dose of estrogen. Estrogen-induced triglyceride enrichment of HDL and LDL was not reversed by the progestin. Conclusions: The only significant quantitative difference in lipoprotein levels between the doses of conjugated equine estrogen before or after administration of medroxyprogesterone acetate was a greater decline in HDL cholesterol levels with the lower dose after 4 months of the progestin. This difference was not sustained over time. There were no differences between doses in the estrogeninduced triglyceride enrichment of lipoproteins, and these qualitative changes were not affected by the progestin.
GBR
OBSTET GYNECOL 1994 83/2 (180-183) Objective: To determine the effects of percutaneous estradiol(E2) implants on the collagen composition and maturity in the bone and skin of osteoporotic postmenopausal women. Methods: Sixteen postmenopausal women with low bone mineral density were treated for I year with 75mg E2 implants. Iliac crest bone and skin biopsies were analyzed for collagen content and collagen cross-links before treatment and at 1 year. Dual energy X-ray absorptiometry of the lumbar spine and proximal femur was also performed before and after 1 year of therapy. Results: The cortical bone showed a significant increase in the mature cross-links of both hydroxylysylpyridinoline (P < 0.01) and lysylpyridinoline (P < O.Ol), with a significant reduction in the percentage of collagen (P < 0.001). The pattern was similar in trabecular bone, with lysylpyridinoline increasing significantly (P c 0.05). The skin exhibited a significant reduction in the immature cross-link hydroxylysinonorleucine (P < O.Ol), but no signiticant change in the percentage of collagen content or the mature cross-link histidinohydroxylysinonorleucin. The median increases in bone density were 11.5% at the spine and 4.34% at the total hip. The median post-treatment serum E2 level was 639 pmoVL. Quantitative aod qualitative ckanges io lipids, lipoproteins, apolipoproteiaA-I, sod sex hormone-bindingglobulin doe to two doses of coo-ted equine estrogen with and without a progestin Miller V.T.; Muesing R.A.; LaRosa J.C.; Stoy D.B.; Fowler SE.; Stillman R.J. USA OBSTET GYNECOL 1994 8312 (173-179) Objective: To determine whether the quantitative and qualitative effects on lipoproteins differ between two doses of
The iadepeodent effects of exercise sod estrogen on lipids and lipoproteinsin postmenopausalwomen Lindheim S.R.; Notelovitz M.; Feldman E.B.; Larsen S.; Khan F.Y. USA
OBSTET GYNECOL 1994 83/2 (167-172) Objective: To assess the effects of a moderate exercise program with and without oral estrogen replacement on levels of lipids and lipoproteins in postmenopausal women. Methods: One hundred one postmenopausal women were randomized into four groups: control or sedentary (A’= 20), exercise alone (N= 25), estrogen replacement using 0.625 mg conjugated equine estrogen (N = 28), and exercise supplemented with conjugated equine estrogen (N = 28). The exercise groups were placed on a moderate exercise program. Following baseline testing, each group returned at 3 and 6 months for cardiorespiratory fitness testing and serum lipid and lipoprotein profiles. Results: We found a significant decrease in systolic blood pressure (P < 0.05) in all treatment groups. The maximum oxygen uptake increased by 9.0 and 7.8% in the exercise and conjugated equine estrogen/exercise groups, respectively, compared to the other groups (P < 0.05). These responses were seen at both 3 and 6 months. Total exercise time (time spent on the treadmill until exhaustion during testing) significantly increased in the exercise group by 21% (P < 0.01). Exercise alone was associated with significant decreases in total cholesterol (5.2%, P c 0.05), triglycerides (2%, P < 0.05), and low-density lipoprotein (LDL) cholesterol (10%. P < O.Ol), and a significant increase in the high-density lipoprotein (HDL) cholesterol-LDL ratio (17.2%, P < 0.01). Significant changes were noted in these values, as well as increases in HDL cholesterol (16 and 14.8%; P < 0.01) and apolipoprotein At (25.6