Lipoprotein and apoprotein levels in postmenopausal women during treatment with norethisterone
Abstract
Lipoprotein and apolipoprotein levels were monitored in 21 postmenopausal women during 6 months' treatment with norethisterone. There was no significant change in low density lipoprotein (LDL) cholesterol but apoprotein B levels rose significantly (p < 0.001) thus increasing the apoprotein : cholesterol ratio in LDL. High density lipoprotein (HDL) cholesterol levels decreased significantly (p < 0.001) in the first two months and did not change significantly thereafter. The HDL2 subfraction was reduced to a greater extent than the HDL3 subfraction. Apoprotein AI and All levels were both reduced as was the apoprotein AI : AII ratio. The ratios of apoproteins AI and AII to HDL cholesterol were increased. We conclude that norethisterone has an adverse effect on the important risk factors for cardiovascular disease.
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Cited by (22)
To evaluate the impact of metabolic effects of different progestogens on the risk of fatal myocardial infarction is evaluated.
The changes in (apo)lipoproteins obtained from a randomized trial of three hormone therapy regimens were applied to three models for predicting fatal myocardial infarction derived from the apolipoprotein-related mortality risk (AMORIS) study. In our trial, 487 postmenopausal women were randomized to oral estradiol, with sequential addition of two trimegestone (TMG) doses or norethisterone acetate (NETA), and studied at baseline and after 3, 6, and 12 months.
The change from baseline in risk of fatal myocardial infarction, using AMORIS model 3, containing total cholesterol, triglycerides, and apolipoprotein AI, was a 10% reduction for the two TMG doses; NETA had no apparent impact. The differences between treatments were significant at all three time points. When apoB was added in AMORIS model 4, the difference between treatments (5% reduction in the two doses of TMG, compared to NETA) decreased over time, probably due to the effect of dropouts in the NETA group.
This analysis shows different metabolic responses to progestogens in terms of risk of fatal myocardial infarction. Generalization of health benefits or adverse effects seen in trials of hormone therapy to other progestogens could be misleading.
Progesterone inhibits apolipoprotein-mediated cellular lipid release: A putative mechanism for the decrease of high-density lipoprotein
2001, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsIn order to investigate the mechanism for female gonadal hormones to regulate the plasma high-density lipoprotein (HDL) level, the effect of 17β-estradiol and progestogens was examined in vitro on the assembly of HDL by free apolipoprotein A-I (apoA-I) with cellular cholesterol and phospholipid. ApoA-I generated HDL particles by removing cholesterol and phospholipid from human fibroblasts, MRC-5. While 17β-estradiol did not influence this reaction, progesterone suppressed the removal by apoA-I of both cholesterol and phospholipid, with the extent of the inhibition more for cholesterol than phospholipid. Three other synthetic progestogens showed the similar inhibitory effect on the cellular cholesterol release. Cellular cholesterol de novo-synthesized from mevalonolactone entered more into the acyl-esterified cholesterol compartment and less to the unesterified compartment in the presence of progesterone. On the other hand, progesterone did not influence the overall mass ratio of free and esterified cholesterol in the cell. Cell-surface cholesterol was also uninfluenced by progesterone when probed by extracellular cholesterol oxidase reaction or by diffusion-mediated cellular cholesterol release to cyclodextrin. Neither caveolin-1 nor ABCA1 expression was influenced by progesterone. Progesterone thus seems primarily to alter the specific intracellular cholesterol compartment that is related to the apoA-I-mediated HDL assembly. This mechanism might contribute to the decrease of plasma HDL by administration of progestogen in women under hormone replacement therapy.
The effects of oral or transdermal 17β-oestradiol combined with cyclical oral Norethisterone acetate on serum lipoprotein concentrations
2001, Clinica e Investigacion en Ginecologia y Obstetriciaanalizar los efectos de 17 β-estradiol oral frente al transdérmico, administrados ambos con adición secuencial de acetato de noretisterona oral, sobre las concentraciones séricas de lípidos y lipoproteínas en mujeres posmenopáusicas.
análisis abierto, aleatorio, con grupos de estudio paralelos. Se incluyeron 56 mujeres posmenopáusicas, con problemas propios del climaterio, las cuales por lo demás estaban sanas. De éstas, 45 cumplieron los criterios del estudio. Untotal de 45 mujeres posmenopáusicas fueron distribuidas aleatoriamente para recibir 17 β-estradiolestriol oral o bien 17 β-estradiol transdérmico, junto con la adición cíclica de acetato de noretisterona durante 48 semanas. Las concentraciones séricas de colesterol total, triglicéridos, lipoproteínas de alta densidad(HDL), lipoproteínas de baja densidad (LDL), lipoproteínas de muy baja densidad (VLDL), apolipoproteínas y lipoproteínas (a) fueron determinadas basalmente, después de 46 semanas (fase estrogénica sola) y a las 48 semanas (fase estrogénicoprogestágena) de tratamiento.
la terapia oral con estradiol no afectó a las concentraciones de colesterol sérico total durante la fase únicamente estrogénica, pero durante la fase combinada hubo un descenso del 5,29% (p < 0,05) debido a una disminución del 6,89% en los valores decolesterol ligado a lipoproteínas de baja densidad (p < 0,01). La terapia oral también incrementó las concentraciones de triglicéridos séricos en un 14,28% durante la fase únicamente estrogénica (p < 0,05). Durante la fase combinada de terapia transdérmica hubo un descenso del 19,80% en las concentraciones de triglicéridos séricos (p < 0,01) y del 5,92% en los valores de HDL(p < 0,05).El estradiol oral redujo las concentraciones de lipoproteína en un 32,98% durante la fase únicamente estrogénica y en un 36,08% con laadición de acetato de noretisterona (p < 0,01). La terapia transdérmica no tuvo efectos significativos sobre la lipoproteína (a).
aparte de un descenso menor en las concentraciones de HDL3 en mujeres a las cuales se les estaba administrando 17 β-estradiol transdérmico, la coadministración de progestágenos orales en general mejoró, en vez de empeorar, el perfil de lipoproteínas séricas.
to analyse the effects of oral versus transdermal 17 β-oestradiol, both given with the cyclical addition of oral Norethisterone acetate, on serum lipid and lipoprotein levels in postmenopausal women.
Open, randomised parallel study groups, 56 healthy post menopausal women with climacteric complaints were screened. Of these, 45 fulfilled the entry criteria.
The 45 postmenopausal women were randomised to receive either oral 17 β-oestradiol, or transdermal 17 β-oestradiol together with the cyclical addition of Norethisterone for 48 weeks.
Serum levels of total cholesterol, triglycerides, high density lipoproteins (HDL), low density proteins (LDL), very low density lipoproteins (VLDL), apoli-proteins and lipoprotein (a) at baseline, and after 46 weeks (oestrogenic alone phase), and at 48 weeks (oestrogen-progesterone phase) of treatment.
Oral oestradiol therapy did not affect serum total cholesterol levels during the oestrogen alone phase, but during the combined phase there was a 5.29% fall (p<0.05) due to a 6.89% decrease in LDL cholesterol levels (p<0.01). Oral therapy also increased serum triglyceride levels by 14.28% during the oestrogen alone phase (p<0.05). During the combined phase of transdermal therapy, there was a 19.80% fall in serum triglyceride levels (p<0.01) and a 5.29% fall in HDL levels (p<0.05). Oral oestradiol reduced lipoprotein (a) levels by 32.08% during the oestrogen alone phase and by 36.08% with the addition of Norethisterone acetate (p<0.01). Transdermal therapy had no significant effect on lipoprotein (a).
Other than a minor fall in HDL3, women receiving transdermic 17 β-oestradiol in co-administration with oral progesterone generally improved, rather than worsened, the serum lipoprotein profile.
Selective oestrogen receptor modulators
1999, Current Obstetrics and GynaecologyThe relevance of hormone-replacement therapy (HRT) in the treatment of the short- and long-term complications of the menopause has become clearly evident. This treatment, however, has been associated with the emergence of complications, namely breast cancer and endometrial neoplasia.
These side effects have led to research in the direction of tissue-specific effects leading to the evolution of selective oestrogen receptor modulators (SERMs). Tamoxifen was the first SERM employed in the prevention of breast cancer recurrence. Although anti-oestrogenic to the breast tissue, tamoxifen was found to maintain bone mass and preserve a favourable lipoprotein profile. Tamoxifen, however, led to endometrial stimulation with consequent polyp formation and hyperplasia.
Raloxifene, a more recent SERM appears to have similar effects as tamoxifen on breast tissue, bone density and the lipoprotein profile. However, unlike tamoxifen, raloxifene does not appear to stimulate the endometrium – on the contrary it appears to be anti-oestrogenic to the endometrial epithelium. A more recent SERM, droloxifene appears to have a more anti-oestrogenic effect to the endometrium with bone sparing effects.
Raloxifene has not been shown to improve on the short-term effects of the menopause, such as hot flushes and sweats. Similar to HRT, there appears to be a slight risk for deep vein thrombosis with raloxifene treatment.
Tibolone is a SERM-like compound with beneficial effects on both the short- and the long-term complications of the menopause. Tibolone appears to have a beneficial influence of hot flushes, bone density and the lipoprotein profile. Conversely, tibolone does not appear to stimulate significantly either breast or endometrial tissue.
SERMS and SERM-like compounds appear to have a promising future for the treatment and prevention of menopausal complications. Clinical proof for the affectiveness is still required. Possibly with further pharmacological manipulation more modern SERMS may be able to reduce both the short- and long-term complications of the menopause and simultaneously reduce the incidence of neoplasia such as breast and uterine carcinoma.
Effects of postmenopausal estrogen/progestin replacement therapy on LDL particles; comparison of transdermal and oral treatment regimens
1996, AtherosclerosisThe aim of the study was to compare the effects of continuous oral estrogen/progestin therapy to the effects of transdermal estrogen therapy combined with cyclic oral progestin on the properties of LDL particles. Eighty postmenopausal women were randomly allocated to receive either oral (continuous 17-beta-estradiol 2 mg and norethisterone acetate 1 mg per day, E2/NETA) or transdermal therapy (patches delivering continuous 17-beta-estradiol, E2, 0.05 mg/day with sequential oral medroxyprogesterone acetate, MPA, 10 mg/day for 12 days/cycle). The groups had similar mean values and ranges of age, BMI and postmenopausal status. The blood samples were taken at baseline, and twice at 1 year before and after MPA administration. LDL particle size distribution was determined by gradient gel electrophoresis and LDL was isolated by sequential ultracentrifugation for compositional analyses. Concentrations of total LDL mass, LDL cholesterol and LDL protein decreased in the oral treatment group (p < 0.01, p < 0.001 and p < 0.01, respectively), whereas they remained unchanged during the transdermal therapy. Particle size of the major LDL peak remained unchanged during both transdermal and oral therapies. HDL cholesterol concentration decreased significantly in both treatment groups (p < 0.001 for both). Serum triglyceride and HDL cholesterol concentrations were the strongest determinants of LDL particle size (r = − 0.50 and r = 0.54, respectively, p < 0.001 for both). The cholesteryl esters and free cholesterol content of the LDL particles decreased in the oral treatment group (p < 0.05). Phospholipid content of LDL increased in both groups receiving either oral or transdermal therapy (p < 0.01 for both). In conclusion, oral administration of 17-beta-estradiol and norethisterone acetate caused a decrease in LDL mass by decreasing the number and cholesterol content of LDL particles. The concomitant decrease of HDL cholesterol by progestins may partly negate this beneficial effect of LDL lowering.
Androgen and progestagen effects on plasma lipids
1995, Progress in Cardiovascular DiseasesAndrogens are 19-carbon steroid rings. Progestagens include both 19-carbon and 21-carbon steroid rings; the 19-carbon progestagens are generally more androgenic than are the 21-carbon compounds. Both androgens and progestagens are physiological regulators of plasma lipids, particularly high-density lipoprotein (HDL) cholesterol. The structure of a particular hormonal preparation, as well as its route of administration, modulates its regularory effects. Both endogenous and exogenous androgens have a suppressive effect on HDL cholesterol in males, with little effect on other plasma lipoproteins. Oral and nonaromatizable androgens have a greater suppressive effect on HDL cholesterol, particularly on HDL2, than do aromatizable androgens. Cross-sectional studies in males generally show a positive relationship between serum T and plasma HDL levels; data in females suggest an inverse relationship between androgens and HDL cholesterol. Medroxy-progesterone acetate and related progestagens have a mild suppressive effect on plasma HDL levels. The C-19 compounds have a greater suppressive effect on HDL cholesterol and the HDL2 density subfraction.