Low-dose oral contraceptives lower plasma levels of apolipoprotein E

Three different oral contraceptive preparations were studied before and after a 3 month treatment period with respect to their effects on plasma lipoprotein parameters. A total of 58 healthy women requesting oral contraception were randomly assigned to three groups. Each woman received either monophasic preparations containing ethinylestradiol and desogestrel (M-DG); ethinylestradiol and gestodene (M-GD); or a triphasic preparation of ethinylestradiol and levonorgestrel (T-LN). As has been reported in other studies, the concentrations of total plasma cholesterol and apolipoproteins B and A-IV did not change significantly in any group. HDL cholesterol, triglycerides, apolipoproteins A-I and A-II increased or tended to increase. Despite the effects of the three hormone preparations on these lipoprotein parameters, however, each led to a highly significant decrease in apolipoprotein E plasma levels. Considering the recently reported observations that oral contraceptives increase the hepatic uptake of cholesterol-rich remnants, this decrease in apo-E plasma levels may in women that take oral contraceptives be directly correlated with increased hepatic lipoprotein metabolism.     

Post-menopausal hormone therapy reduces autoantibodies to oxidized apolipoprotein B100

The aim of the study was to verify whether post-menopausal hormone replacement therapy (HRT) modifies autoantibody titers against oxidized low-density lipoprotein (LDL) (anti-LDLoxi), against epitopes of oxidized apolipoprotein B100 and common carotid intima-media thickness (IMT) in these women. Sixty-eight women in pre-menopause (PMW) and 216 in post-menopause (POMW) were recruited; eighty-three had undergone HRT for at least 12 months, where 48 received conjugated estrogens alone (EHRT) and 35 received conjugated estrogen and medroxyprogesterone acetate (CHRT). ELISA was used to determine autoantibodies. Lipoprotein lipase (LPL), hepatic lipase (HL), cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities were assayed by radiometric methods. IMT was measured using Doppler ultrasound. Anti-oxidized LDL and anti-D antibodies increased by 40% (p?≤?0.003) and 42% (p?≤?0.006), respectively, with menopause. There was a surprising and significant 7% reduction in anti-D2 antibody titers with HRT (p?≤?0.050), indicating a positive effect of treatment on the immune response to oxidized LDL. Combined HRT decreased activities of HL and LPL. HRT did not change common carotid IMT, which was increased by 32% as expected after menopause (p?≤?0.030). This study describes, for the first time, the protective effect of HRT on decreasing autoantibody titers against oxidized apolipoprotein B in LDL.     

Changes in apolipoprotein AI after treatment with high-dose medroxyprogesterone acetate

21 women (mean age 60 years, range 48-72) were given depot medroxyprogesterone acetate (DMPA), 1,000 mg/week parenterally for 6 months, as part of the treatment for endometrial carcinoma in either clinical stage I or II. Before treatment and after 1, 3 and 6 months of treatment serum apolipoprotein AI was analyzed by electroimmunoassay. There was a significant decrease in apolipoprotein AI after the administration of DMPA, compared to the value before treatment. A low level of apolipoprotein AI is considered a risk factor for the development of atherosclerosis and cardiovascular disease. Such a risk might therefore be anticipated if the period of treatment was extended to several years.     

Expression and clinical significance of apolipoprotein D in epithelial ovarian carcinomas

OBJECTIVE: Apolipoprotein D is a protein component of the human plasma lipid transport system but is also associated with a more favorable prognosis in women with breast cancer. This retrospective study was undertaken to examine the tumoral expression of apolipoprotein D in epithelial ovarian cancer and to analyze the possible correlation with tumor and patient characteristics as well as androgen receptors and their prognostic significance. METHODS: Immunohistochemical evaluation was used to examine apolipoprotein D expression in paraffin blocks from 68 epithelial ovarian carcinomas. RESULTS: A total of 18 (26.4%) tumors stained positively. No significant correlation was found between apolipoprotein D expression and patient or tumor characteristics and androgen receptor status. However, apolipoprotein D expression was significantly associated with prognosis in patients with residual tumor greater than 1 cm. Thus, patients with apolipoprotein-D-negative tumors had a poorer overall survival than those with apolipoprotein-D-positive tumors (P = 0.039). In addition, multivariate analysis demonstrated that apolipoprotein D expression was an independent prognostic factor with initial tumor size in this group of patients (P = 0.005). CONCLUSIONS: Our results led us to consider the existence of apolipoprotein D expression by a significative percentage of ovarian carcinomas, and this protein expression might be of clinical usefulness for identifying lesions with different evolution.     

The effect of hormone replacement therapy on the levels of serum lipids, apolipoprotein AI, apolipoprotein B and lipoprotein (a) in Turkish postmenopausal women

Objectives Estrogen replacement therapy alters the lipid profiles favorably for delaying atherosclerosis in postmenopausal women. The effects of estrogen plus progesterone combination therapy on lipids are controversial. This study was designed to evaluate the effect of female sex hormones on lipids and lipoproteins and to clarify the influence of progesterone on the effect of estrogen in postmenopausal women.Methods Of the 60 postmenopausal women admitted to our menopause clinic, 40 had intact uterus and received continuous 0.625 mg conjugated equine estrogen (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA), whereas the remaining 20 were hysterectomized and received 0.625 mg CEE daily. To assess the alterations in lipids and lipoproteins during menopause, 45 healthy premenopausal women were investigated. Lipid and lipoprotein levels were assessed in each subject at baseline and at the 6th and 18th months of therapy.Results In menopause, a shift towards more atherogenic lipid and lipoprotein profiles than those of the premenopausal state was found. Following 18 months of treatment, both regimens reduced total cholesterol (TC) levels as compared with the baseline (6.4 vs. 6.9% in the CEE/MPA and CEE groups, respectively). The CEE group had a more pronounced increase in high-density lipoprotein (HDL) cholesterol than the CEE/MPA group (10.3 vs. 8.8%, respectively). Both groups displayed reduced TC, low-density lipoprotein (LDL) cholesterol and apolipoprotein-B (ApoB) concentrations, whereas triglycerides increased, with a greater tendency to increase in the CEE/MPA group at the end of the trial. Also, the lipoprotein (a) [Lp(a)] levels decreased significantly (27.6 vs. 24.5% in the CEE/MPA and CEE groups, respectively). This decrease was more pronounced in subjects with a relatively higher basal Lp(a) concentration.Conclusion Both treatment regimens caused positive alterations in the lipid and lipoprotein profiles. This association might play a pivotal role in the postmenopausal increases in atherosclerotic diseases and cardioprotective effect of estrogen in postmenopausal women.     

Differential reproductive efficiency associated with common apolipoprotein e alleles in postreproductive-aged subjects

OBJECTIVE: To investigate the possible impact of apolipoprotein E (APOE) polymorphism on reproductive efficiency. DESIGN: Population study. SETTING: University Departments and a Laboratory of National Research Council. PATIENT(S): One hundred sixty healthy unrelated subjects of postreproductive age. INTERVENTION(S): Peripheral blood collection and questionnaire administration. MAIN OUTCOME MEASURE(S): Apolipoprotein E genotypes were detected after PCR amplification and CfoI digestion; plasma total cholesterol was assayed. RESULT(S): The mean number of children of e*2 allele carriers (2.4) was lower than that of e*3/e*3 and e*4/e*3 subjects (3.9). The trend was similar (2.8 vs. 4.8) when the number of pregnancies was considered. Moreover, there was a clear inverse relationship between number of children and e*2-carrying genotype proportions (chi(2) for trend = 6.3). Conversely, the e*3/e*3 genotype was associated with the highest number of children and pregnancies (3.9 and 4.9, respectively), and the e*4/e*3 genotype, with intermediate values (3.7 and 4.4). Carriers of e*2 allele also showed the lowest levels of total cholesterol. CONCLUSION(S): The e*2 allele seems to be associated with the lowest reproductive efficiency and the e*3 allele, with the highest. The different total cholesterol levels associated with APOE genotypes could have an effect on steroidogenesis and determine as a consequence the observed differential fertility.     

Effect of hormone replacement therapy,tibolone and raloxifene on serum lipids,apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women

The aim of this study was to assess the effect of estrogen, two regimens of continuous combined hormone replacement therapy (HRT), tibolone and raloxifene on serum lipid, apolipoprotein A1 and B and lipoprotein(a) levels in Greek postmenopausal women. A total of 350 postmenopausal women were studied in a prospective open design. Women were assigned to one of the following regimens depending on the presence of risk factors for osteoporosis, climacteric symptoms and an intact uterus: conjugated equine estrogen 0.625 mg (CEE, n=34), continuous combined CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 5 mg, (n=80), continuous combined 17β-estradiol 2 mg plus norethisterone acetate (NETA) 1 mg (n=58), tibolone 2.5 mg (n=83) and raloxifene HCl 60 mg (n=50). Forty-five postmenopausal women with no indications for HRT served as controls. Total cholesterol (TC), low-density lipoprotein (LDL) cholestrol and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein A1 (ApoA₁), apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) levels were assessed in each subject at baseline, and at 6 and 12 months of therapy. All therapy regimens lowered TC levels compared to baseline (4.2-8.0% decrease). This effect was more prominent in the subgoup of women with high baseline TC levels (9.1-20.4% decrease). LDL cholesterol decreased significantly in CEE, CEE/MPA and raloxifene groups (?11.2%, ?11.9% and ?11.0%, respectively). Hypercholesterolemic women exhibited a steeper decrease in LDL cholesterol (10.6-27.8% in all therapy groups). TG levels increased significantly in the CEE and CEE/MPA groups (23.7% and 21.8%, respectively), while estradiol/NETA had no effect on TG levels. Tibolone decreased TG levels markedly, by 20.6%, while raloxifene had no TG-lowering effect. HDL cholesterol and ApoA₁ were increased by CEE and CEE/MPA (HDL cholesterol, 7.4% and 11.8%, respectively; ApoA₁, 17.8% and 7.9%, respectively) and decreased by tibolone (HDL cholesterol, ?13.6%; and ApoA₁, ?9.9%). All therapy regimens except raloxifene lowered Lp(a) levels, with tibolone having the more pronounced effect (?13.2 to ?29.0%). In conclusion, each therapy regimen had a different effect on lipid-lipoprotein levels, exerting favorable and unfavorable modifications. Hypercholesterolemic women seemed to benefit more from the cholesterol-lowering effect of estrogen replacement therapy/HRT. The choice for a particular regimen should be based on individual needs, indications and lipid-lipoprotein profile.     

Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women.

The aim of this study was to assess the effect of estrogen, two regimens of continuous combined hormone replacement therapy (HRT), tibolone and raloxffene on serum lipid, apolipoprotein A1 and B and lipoprotein(a) levels in Greek postmenopausal women. A total of 350 postmenopausal women were studied in a prospective open design. Women were assigned to one of the following regimens depending on the presence of risk factors for osteoporosis, dimacteric symptoms and an intact uterus: conjugated equine estrogen 0.625 mg (CEE, n = 34), continuous combined CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 5 mg, (n = 80), continuous combined 17beta-estradiol 2 mg plus norethisterone acetate (NETA) 1 mg (n = 58), tibolone 2.5 mg (n = 83) and raloxifene HCl 60 mg (n = 50). Forty-five postmenopausal women with no indications for HRT served as controls. Total cholesterol (TC), low-density lipoprotein (LDL) cholestrol and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) levels were assessed in each subject at baseline, and at 6 and 12 months of therapy. All therapy regimens lowered TC levels compared to baseline (4.2-8.0% decrease). This effect was more prominent in the subgoup of women with high baseline TC levels (9.1-20.4% decrease). LDL cholesterol decreased significantly in CEE, CEE/MPA and raloxifene groups (-11.2%, -11.9% and -11.0%, respectively). Hypercholesterolemic women exhibited a steeper decrease in LDL cholesterol (10.6-27.8% in all therapy groups). TG levels increased significantly in the CEE and CEE/MPA groups (23.7% and 21.8%, respectively), while estradiol/NETA had no effect on TG levels. Tibolone decreased TG levels markedly, by 20.6%, while raloxifene had no TG-lowering effect. HDL cholesterol and ApoA1 were increased by CEE and CEE/MPA (HDL cholesterol, 7.4% and 11.8%, respectively; ApoA1, 17.8% and 7.9%, respectively) and decreased by tibolone (HDL cholesterol, -13.6%; and ApoA1, -9.9%). All therapy regimens except raloxifene lowered Lp(a) levels, with tibolone having the more pronounced effect (-13.2 to -29.0%). In conclusion, each therapy regimen had a diferent effect on lipid-lipoprotein levels, exerting favorable and unfavorable modifications. Hypercholesterolemic women seemed to benefit more from the cholesterol-lowering effect of estrogen replacement therapy/HRT. The choice for a particular regimen should be based on individual needs, indications and lipid-lipoprotein profile.     

Synthesis and secretion of apolipoprotein E by human placenta and choriocarcinoma cell lines

The synthesis and secretion of apolipoproteins (apos) by cells from a human choriocarcinoma cell line, JAR, were examined by [35S]-methionine labeling followed by immunoprecipitation and SDS/PAGE. Apo E, but not apos A-I, A-IV, or B, was synthesized and secreted. Apo E was also synthesized by fragments of chorionic villi from human placenta and by another choriocarcinoma line, BeWo. Pulse-chase experiments with JAR cells revealed that apoE was initially synthesized as a 33 kDa protein followed by a 34 KDa protein, probably the result of glycosylation. The latter was secreted into the medium where it was detected coincident with a 21/22 kDa doublet, possibly proteolytic fragments of apo E. Approximately 50 per cent of the apo E in the medium was complexed with lipid as indicated by ultracentrifugation at a density of 1.21 g/ml. The amount of apo E produced by JAR was not affected by preincubation with dibutyryl cAMP and theophylline, or by the cholesterol content of the cells. Following perfusion of an isolated lobule of human placenta with [14C]-amino acids, [14C]-apo E was detected by immunoprecipitation of the maternal and fetal perfusates with 88 per cent in the maternal perfusate. These studies suggest that apo E, which promotes receptor-mediated lipoprotein uptake, is secreted by the trophoblast to facilitate uptake of maternal lipoproteins.     

Cell-type specific expression and regulation of apolipoprotein D and E in human endometrium

Objective

To assess the expression and regulation of antilipoprotein D (ApoD) and antilipoprotein E (ApoE) in human endometrium.

Study design

Endometrial biopsies from healthy, regularly cycling women were collected during the late proliferative and mid-secretory phase. mRNA gene expression of ApoD and ApoE was determined using real-time PCR in whole tissue, in isolated stromal (ESC), epithelial (EEC) and CD45⁺ leukocytes (EIC), as well as after hormonal stimulation of ESC and EEC in vitro. Protein expression was analyzed using immunohistochemistry.

Results

ApoD and ApoE mRNA was expressed in all cell types examined. A rise in ApoD mRNA expression was seen in whole endometrium, ESC, and EEC in the secretory phase, as well as after hormonal stimulation of ESC and EEC in vitro. ApoE mRNA was significantly upregulated in whole endometrium of secretory phase biopsies, while its expression was not altered by progesterone in vitro. Immunohistochemistry of whole endometrial tissue localized ApoD mainly in ESC and EEC. While ApoE was localized slightly in ESC, it was particularly noted on the surface of secretory phase endothelial cells.

Conclusion

We demonstrate for the first time the cell-type and cycle dependent expression of ApoD and ApoE within human endometrium, suggesting their role in endometrial modulation.     

Distribution of apolipoprotein(a) isoforms in normotensive and severe preeclamptic women

OBJECTIVE: Preeclampsia is a pregnancy-related disorder constituting one of the primary causes of worldwide maternal and fetal mortality, but despite intensive research its pathogenesis remains unclear. Lipids have been implicated in the development of preeclampsia, although this possible association remains controversial and not yet fully investigated. This study set out to examine the potential association between lipoprotein(a) and the development of severe preeclampsia. The focus of this study was to investigate the potential utility of apolipoprotein(a) isoforms as possible diagnostic markers for identifying women at risk for developing preeclampsia. METHODS: Study participants included a control group of nonpregnant female volunteers (n = 59), a group of healthy pregnant (normotensive) female volunteers (n = 51), and a group of severe preeclamptic female volunteers (n = 59). Serum lipoprotein(a) concentrations were measured using double-antibody ELISA methods and were found to be 17.0+/-23.6 mg/dl among nonpregnant controls (n = 51), 15.9+/-15.8 mg/dl among healthy pregnant normotensives (n = 51), and 16.2+/-16.7 mg/dl in the preeclamptic group (n = 59). In addition, apolipoprotein (a) isoforms were identified using high-resolution SDS-agarose electrophoresis followed by immunoblotting. RESULTS: We detected no significant differences between the groups studied in the distribution of isoforms (Chi-square = 1.21, df = 4, P = 0.89); however, in a 1-week interval we detected a 42.2% rise in Lp(a) levels as well as a 67.1% rise in C-reactive protein concentrations among 10 volunteers in the preeclamptic group (median = 9.6; P < 0.05). CONCLUSIONS: Although the exact mechanism of pathogenesis continues to elude investigators, our results suggest that lipoprotein(a) may act as an acute-phase reactant during preeclampsia. Although our results are preliminary, they are consistent with growing evidence implicating lipids as among those factors involved in the etiology of preeclampsia. Changes in apolipoprotein(a) may be among those important biochemical markers that are found to be useful in the early identification of high-risk women and warrant further study.     

Distribution of apolipoprotein(a) isoforms in normotensive and severe preeclamptic women

Objective: Preeclampsia is a pregnancy-related disorder constituting one of the primary causes of worldwide maternal and fetal mortality, but despite intensive research its pathogenesis remains unclear. Lipids have been implicated in the development of preeclampsia, although this possible association remains controversial and not yet fully investigated. This study set out to examine the potential association between lipoprotein(a) and the development of severe preeclampsia. The focus of this study was to investigate the potential utility of apolipoprotein(a) isoforms as possible diagnostic markers for identifying women at risk for developing preeclampsia.

Methods: Study participants included a control group of nonpregnant female volunteers (n = 59), a group of healthy pregnant (normotensive) female volunteers (n = 51), and a group of severe preeclamptic female volunteers (n = 59). Serum lipoprotein(a) concentrations were measured using double-antibody ELISA methods and were found to be 17.0 ± 23.6 mg/dl among nonpregnant controls (n = 51), 15.9 ± 15.8 mg/dl among healthy pregnant normotensives (n = 51), and 16.2 ± 16.7 mg/dl in the preeclamptic group (n = 59). In addition, apolipoprotein (a) isoforms were identified using high-resolution SDS-agarose electrophoresis followed by immunoblotting.

Results: We detected no significant differences between the groups studied in the distribution of isoforms (Chi-square = 1.21, df = 4, P = 0.89); however, in a 1-week interval we detected a 42.2% rise in Lp(a) levels as well as a 67.1% rise in C-reactive protein concentrations among 10 volunteers in the preeclamptic group (median = 9.6; P < 0.05).

Conclusions: Although the exact mechanism of pathogenesis continues to elude investigators, our results suggest that lipoprotein(a) may act as an acute-phase reactant during preeclampsia. Although our results are preliminary, they are consistent with growing evidence implicating lipids as among those factors involved in the etiology of preeclampsia. Changes in apoliprotein(a) may be among those important biochemical markers that are found to be useful in the early identification of high-risk women and warrant further study.     

Lipoprotein and apolipoprotein levels in postmenopausal women on continuous oestrogen/progestogen therapy

Levels of serum lipoproteins and apolipoproteins were monitored for 48 weeks in two groups of women taking part in a double-blind trial of continuous oestrogen/progestogen with and without oestriol. There were no differences between the effects of the two treatments on the substances measured. Triglycerides did not change and there was a transient fall in very low density lipoprotein cholesterol. Low density lipoprotein cholesterol fell over the first 24 weeks but rose thereafter to pretreatment levels. There was a decrease in high density lipoprotein (HDL) cholesterol due to a transient fall in HDL2 cholesterol and a gradual decrease in HDL3 cholesterol. Consequently, the only change in lipid levels present after 48 weeks was a decrease in HDL3 cholesterol, the clinical significance of which is uncertain. There was, however, an increase in apoprotein B levels and decreases in apoprotein AI and AII levels. These alterations in apoprotein levels may be unfavourable, since apoprotein B levels have been positively correlated and apoprotein AI and AII levels negatively correlated with coronary heart disease.     

Relationship between serum estrogen and level of apolipoprotein E in human ovarian follicular fluid

Apolipoprotein E (apoE) is an important effector of plasma lipoprotein due to its interaction with cell-surface receptors. In addition, it is secreted by rat and human ovarian granulosa cells in tissue culture, and its production is hormonally modulated. Such observations indicate that apoE should be found in human follicular fluid (FF) and that its abundance therein may be subject to hormonal regulation. The authors have collected FF from seven normally cycling women by needle puncture at the time of laparoscopy and from hyperstimulated ovaries of four women undergoing in vitro fertilization (IVF). Apolipoprotein E is present in human FF. The ratio of apoE concentration in FF to that in serum, as determined by western blot analysis, ranges from 0.43 to 4.2 for the normally cycling patients and from 0.16 to 0.77 for the IVF patients. Serum estrogen levels (range, 42 to 477 pg/ml) for the cycling patients are inversely correlated with the FF-to-serum ratio of apoE (r = 0.91). The content of apoE in FF, relative to serum, thus falls dramatically as the follicle approaches ovulation. These data, plus the known ability of apoE to carry cholesterol and other lipids, suggest an important role for apoE in the ovary.     

Cord serum lipid and apolipoprotein levels in preterm infants with the neonatal respiratory distress syndrome

Objective: The purpose of this study was to evaluate the effects of birth weight on cord serum lipid and apolipoprotein levels in preterm infants with and without respiratory distress syndrome (RDS). Methods: Cord serum lipid and apolipoprotein levels were evaluated in preterm infants (39 with RDS and 68 controls without RDS). Based on morbidity and mortality risk, RDS and non-RDS infants were separated into four birth weight groups (2000-2499 g, 1500-1999 g, 1000-1499 g, < 1000 g) and evaluated for effects of birth weight on cord serum levels. Results: RDS infants with birth weight of 2000-2499 g had significantly higher levels of cholesterol, triglyceride, total fatty acids and apolipoprotein A-I, but not arachidonic acid, than controls. RDS infants weighing 1000-1999 g had lower total fatty acids and apolipoprotein B levels, including arachidonic acid, than non-RDS infants. Cord serum lipid and apolipoprotein levels were significantly elevated in large (2000-2499 g) RDS infants, but lower levels were found in smaller (1000-1999 g) RDS infants. Conclusions: Cord serum arachidonic acid and apolipoprotein levels found in RDS infants suggest that lipid transport across the placenta may be abnormal. Inadequate total fatty acid supplies in utero could interfere with normal fetal growth and maturation, leading to development of neonatal RDS as one manifestation of risk for postnatal morbidity and mortality.