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To investigate long-term lipid and lipoprotein changes in postmenopausal women treated with tibolone in a prospective study using appropriate control groups.Seventy-six of 105 postmenopausal women initially selected for this study completed the 2-year follow-up. Patients were allocated into three groups. The first received 2.5 mg/day tibolone continuously (n = 27; group T), the second received 0.625 mg/day conjugated equine estrogen plus 2.5 mg/day of medroxyprogesterone (group E-P) continuously (n = 25), and a third group contained an additional 24 women who did not receive replacement therapy; these constituted the untreated control group (group C). Plasma lipids and lipoproteins were determined in all patients before joining the study and also at 12 and 24 months after being included.Women treated with tibolone experienced the greatest decreases in cholesterol, both total and high density lipoprotein (HDL), and triglycerides (TG), whereas the highest increase in HDL was observed in the group E-P. A decrease in low density lipoprotein levels was detected in both therapy groups, whereas a significant increase was observed in the control group. TG were increased after E-P therapy. In all the groups, apolipoprotein AI showed parallel trends to HDL and apolipoprotein B to low density lipoprotein.Both therapy groups, tibolone and E-P, induced changes in levels of plasma lipids, lipoproteins and apolipoproteins. Long-term tibolone treatment is associated with a marked and significant decrease in HDL apolipoprotein AI and TG, an effect that defines the major difference with standard HRT. Clearly, further studies are necessary to establish the definite risk/benefit ratio of tibolone with respect to its overall effect on lipid metabolism.

To evaluate plasma lipids, lipoproteins and apolipoprotein changes induced by gestational diabetes.In this case-control study, 60 women between 26 and 32 weeks of pregnancy were allocated to four groups according to lipid status and glucose tolerance: (1) normolipemia and no gestational diabetes, (2) normolipemia and gestational diabetes, (3) hyperlipemia and no gestational diabetes, and (4) hyperlipemia and gestational diabetes. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low density lipoprotein cholesterol (VLDLc), triglycerides, triglycerides/very low density lipoprotein (VLDL), apolipoproteins (APO) A1 and APO B, APO B-VLDL and APO B/low-density lipoprotein were measured.There were no statistically significant differences in the normolipemic group of women. Among the hyperlipemic patients, gestational diabetic women showed lower VLDLc when compared to nondiabetic patients.Our results, comparing groups separated groups by lipid status, show that the only difference in lipid profile associated with glucose intolerance is lower VLDLc in hyperlipemic patients.

To assess whether the effects on plasma lipids and lipoproteins after oophorectomy differ in patients who receive transdermal estrogen replacement therapy (ERT) with and without progestin.Twenty-five healthy, normal-weight, regularly menstruating women who underwent hysterectomy and bilateral oophorectomy for benign diseases received, for one year, transdermal therapeutic systems containing estradiol with daily delivery of 50 micrograms cyclically for 24 days per month plus 2.5 mg/d of oral medroxyprogesterone acetate (MPA) sequentially for the last 12 days of each cycle. After the first year the patients ceased to take MPA. We determined the levels of cholesterol (CHOL), high density lipoprotein (HDL)-CHOL, low density lipoprotein (LDL)-CHOL, triglycerides (TG) and apolipoproteins (apo) A-I and B prior to oophorectomy, one month after surgery and during the 6th and 12th months on estrogen plus progestogen substitution and during the 18th and 24th months without progestogen addition.After oophorectomy, the patients showed increases in LDL, apo-B and atherogenic index, whereas after hormone replacement therapy the patients exhibited falls in plasma LDL, apo-B and atherogenic index and increases in HDL and apo A-I. No significant changes in total CHOL were observed after surgery or treatment, and TG were decreased. Plasma levels of lipids and lipoproteins during estrogen replacement therapy (ERT) without MPA were not significantly different from those observed during ERT plus MPA.Changes in lipids induced by transdermal ERT were not affected by low doses of MPA.

Several studies have demonstrated that the use of estrogens in postmenopausal women has a protective effect against cardiovascular disease; however, this beneficial effect may be counteracted when concomitant progestogens are administered. We investigated the influence of hormone replacement therapy (HRT) with lower doses of medroxyprogesterone acetate (MPA) (2.5 mg/d) on the endometrium and on the plasma levels of lipids, lipoproteins and apolipoproteins. All the studied HRT regimens induced favorable changes in the levels of plasma lipids, lipoproteins and apolipoproteins, which may play an important role in the prevention of cardiovascular disease. The dosage of 2.5 mg/d of MPA is clearly inadequate to protect the endometrium from hyperplastic changes with sequential regimens, but probably this dosage is safe when MPA is administered continuously.

Neeraj Prabhakar,1,2 Jixi Zhang,3 Diti Desai,1 Eudald Casals,1 Tina Gulin-Sarfraz,1 Tuomas Näreoja,2,4 Jukka Westermarck,5,6 Jessica M Rosenholm1 1Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, 2Laboratory of Biophysics, Faculty of Medicine, University of Turku, Turku, Finland; 3College of Bioengineering, ChongqingUniversity, Chongqing, People’s Republic of China; 4Department of Neuroscience, Karolinska Institute, Stockholm, Sweden; 5Centre for Biotechnology, University of Turku and Åbo Akademi, 6Department of Pathology, University of Turku, Turku, Finland Abstract: Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with the challenge being to deliver it in a sustained manner. The combination of mesoporous silica nanoparticles (MSNs) and polycations in the confined pore space allows for incorporation and controlled release of therapeutic siRNA payloads. We hereby constructed MSNs with expanded mesopores and pore-surface-hyperbranched poly(ethyleneimine) (PEI) tethered with redox-cleavable linkers that could carry a high payload of siRNA (120mg·g-1). The developed nanocarriers were efficiently taken up by cancer cells and were subsequently able to escape to the cytoplasm from the endosomes, most likely owing to the integrated PEI. Triggered by the intracellular redox conditions, the siRNA was sustainably released inside the cells over a period of several days. Functionality of siRNAs was demonstrated by using cell-killing siRNA as cargo. Despite not being the aim of the developed system, in vitro experiments using cell-killing siRNAs showed that the efficacy of siRNA transfection was comparable to the commercial in vitro transfection agent Lipofectamine. Consequently, the developed MSN-based delivery system offers a potential approach to hybrid nanocarriers for more efficient and long-term siRNA delivery and, in a longer perspective, in vivo gene silencing for RNA interference (RNAi) therapy. Keywords: mesoporous silica nanoparticles, RNAi therapy, siRNA delivery, stimuli-responsive drug release, hybrid nanocarriers