Leuprolide acetate induces structural and functional recovery of injured spinal cord in rats

Gonadotropin-releasing hormone (GnRH) and its synthetic analog leuprolide acetate, a GnRH agonist, have neurotrophic properties. This study was designed to determine whether administration of leuprolide acetate can improve locomotor behavior, gait, micturition reflex, spinal cord morphology and the amount of microglia in the lesion epicenter after spinal cord injury in rats. Rats with spinal cord compression injury were administered leuprolide acetate or saline solution for 5 weeks. At the 5^th week, leuprolide acetate-treated rats showed locomotor activity recovery by 38%, had improvement in kinematic gait and exhibited voiding reflex recovery by 60%, as compared with the 1^st week. By contrast, saline solution-treated rats showed locomotor activity recovery only by 7%, but voiding reflex did not recover. More importantly, leuprolide acetate treatment reduced microglial immunological reaction and induced a trend towards greater area of white and gray matter in the spinal cord. Therefore, leuprolide acetate has great potential to repair spinal cord injury.     

Glial dysfunction in abstinent methamphetamine abusers

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized ¹³C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects (P>0.1). However, glial ¹³C-bicarbonate production rate from [1-¹³C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamine-addicted women (methamphetamine 0.04 μmol/g per min (N=5) versus controls 0.11 μmol/g per min (N=5), P=0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous ¹³C MRS methods may determine ‘cause and effect'' between glial failure and neuronal injury.     

Pharmacokinetics and drug interactions of eslicarbazepine acetate

Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11 position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11-epoxide. Unlike OXC, which is metabolized to both eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to eslicarbazepine. The systemic exposure to eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t(1/2,eff) ) of eslicarbazepine was 20-24 h, which is approximately two times longer than its terminal half-life (t(1/2)). At clinically relevant doses (400-1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin.     

The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits – an attempt to interpret the Women's Health Initiative results

The results of the two arms of the Women's Health Initiative (WHI) study allow a comparative assessment of the contribution of the progestogen component to the changes in risk of cardiovascular disease and cancer during treatment of postmenopausal women with conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). However, the high proportion of older and overweight or obese women compromises any conclusions, since we estimate that 50% of the women would have the metabolic syndrome. In overweight postmenopausal women with hyperinsulinemia, the risk of breast cancer is elevated and cannot be increased further by hormone replacement therapy (HRT). Therefore, the non-significant, but consistent reduction in breast cancer risk during treatment with CEE alone might be based on an improvement of hyperinsulinemia. The 24% increase in breast cancer risk in the CEE/MPA group can be regarded as an artifact due to very low numbers of breast cancer diagnoses in the placebo group of women who had received HRT prior to the WHI study. The elevated risk of venous thromboembolism and the transient increase in the risk of coronary heart disease (CHD) during treatment with CEE/MPA but not CEE alone suggests a direct effect of MPA on the vessel wall. MPA has been demonstrated to upregulate the thrombin receptor, the thrombin-induced production of tissue factor and procoagulatory activity in the vessel wall owing to its glucocorticoid activity. In contrast, CEE alone reduced non-significantly the risk of CHD in women aged 50–59 years, suggesting that primary prevention is possible if estrogen replacement therapy is initiated early. As clinical studies on the effect of different progestogens combined with estrogens are scarce, a possible superiority of progestogens other than MPA remains to be proven.     

Effect of ethinylestradiol/cyproterone acetate on endothelial function in young non-obese women with polycystic ovary syndrome: a pilot study

Background.?Combined oral contraceptives are used in polycystic ovary syndrome (PCOS) women for the treatment of hyperandrogenism and menstrual cycle disturbances.

Aim.?To assess the effect of ethinylestradiol and cyproterone acetate (EE/CA) on endothelial function in young, non-obese PCOS women in a pilot study.

Methods.?Thirteen young, non-obese PCOS women (20.9?±?3.7 years, 23.0?±?4.0?kg/m²) received 35?mcg EE & 2?mg CA for 6 months. Fourteen age- and body mass index (BMI)-matched healthy women served as controls. Endothelial function assessed by brachial artery flow-mediated dilation (FMD), indices of hyperandrogenism, and insulin resistance were studied at baseline and 6-month follow-up.

Results.?FMD was impaired in PCOS compared to control women (4.67?±?2.38% vs. 10.12?±?3.19%, p?<?0.001), but increased significantly following EE/CA (9.99?±?2.11%, p?<?0.001 vs. baseline), reaching normal values (p?=?NS vs. controls). EE/CA also significantly decreased hyperandrogenism indices and increased total and HDL cholesterol and triglycerides (p?<?0.05 vs. baseline). The only independent predictor of treatment-induced FMD improvement in PCOS women was the decrease in free androgen index.

Conclusions.?Treatment with combination of estrogens and antiandrogens reverses endothelial dysfunction in young, non-obese PCOS women mainly via improving hyperandrogenism. Further research is needed to investigate whether this treatment may also reduce cardiovascular risk in these women.     

Assessment of mammographic density in postmenopausal women during long term hormone replacement therapy

Abstract

Objective: To assess long-term effects of different hormone replacement therapy (HRT) regimens on mammographic density.

Methods: One hundred sixty-five postmenopausal women were treated with the same HRT during 5 years: 38 received transdermal estradiol, 78 cyclic combined therapy and 49 continuous combined therapy. Mammograms were obtained at baseline, at 1-year and 5-year treatment. Breast density changes were categorized as slight focal increased density, considerable focal increased density, slight diffuse increased density and considerable diffuse increased density.

Results: Mammographic density increased in 7.9% of women receiving estrogen alone versus 25.2% of women receiving combined therapy (p?<?0.022) during 1 year, and in 7.9% of women versus 28.3% of women (p?<?0.009) after 5 years of therapy, respectively. There were significant statistical differences in women treated with estrogen alone versus those treated with combined HRT after 1 and 5 years. After 5 years of HRT, breast density increased 21.8% in women receiving cyclic combined therapy versus 38.8% in those under continuous combined therapy (p?<?0.039).

Conclusion: An increase in breast density is significantly more frequent in women receiving combined estrogen-progestin therapy than in women receiving estrogen alone. There are differences between cyclic and continuous combined therapy at 5 years of treatment.     

Systemic hormonal modulation induces sperm nucleosomal imbalance in rat spermatozoa

Sperm chromatin packaging is a very complex and highly regulated phenomenon. While most of the sperm chromatin is replaced by protamines, some are retained in nucleosomes. It is recently being recognised that these nucleosomes are intentionally retained and could be contributing to the expression of genes in the very early stages of embryogenesis. Endocrine disruption has been previously shown to affect reproductive outcome and sperm DNA methylation. This study aims to decipher the possibility of changes in nucleosome occupancy in sperm chromatin, induced by tamoxifen (selective oestrogen receptor modulator) and cyproterone acetate (androgen antagonist). We used next‐generation sequencing approach (MNase‐Seq) to identify changes in the nucleosome landscape of the spermatozoa. We demonstrated that endocrine disruption affects nucleosome occupancy at critical regions of the genome and many of them harbour genes relevant for embryogenesis. This study emphasises that environmental factors could affect embryo development by way of modulating male epigenetic factors.     

腹腔镜手术前后联合醋酸亮丙瑞林治疗子宫内膜异位症的比较研究

目的探讨腹腔镜手术与促性腺激素释放激素激动剂（GnRH-a）醋酸亮丙瑞林联合治疗子宫内膜异位症（endometriosis,EM）的临床价值。方法回顾性分析2004年1月~2008年11月395例EM的临床资料,A组133例为腹腔镜术前使用醋酸亮丙瑞林,3.75 mg皮下注射,每28天一次,3个月后再手术;B组150例为腹腔镜术后使用醋酸亮丙瑞林3个月;C组（对照组）112例单纯行腹腔镜手术。比较三组术中情况及远期预后。结果 （1）A组手术时间及术中出血量较B组及C组明显减少[手术时间：A组（146.8±42.5）min、B组（254.4±51.2）min、C组（243.5±48.8）min,术中出血量A组（76.4±31.2）ml、B组（110.7±29.9）ml、C组（101.3±35.4）ml,P均=0.000]。（2）较之C组,A组及B组的总有效率均显著升高,复发率均明显下降（总有效率：C组47.1%、A组75.6%、B组77.9%,复发率：C组37.5%、A组13.0%、B组12.2%,P均=0.000）,A组与B组之间比较无统计学差异（P=0.671,0.849）。（3）随访2年,三组妊娠率比较,差异无统计学意义[A组47.6%（20/42）,B组51.8%（29/56）,C组37.5%（15/40）,P=0.377]。结论较之单纯腹腔镜手术治疗,腹腔镜手术联合GnRH-a治疗EM能提高有效率,降低复发率,但不能明显提高妊娠率。腹腔镜手术前或手术后用药疗效相似,但术前用药更有利于手术实施。     

Prolonged clinical benefit from the maintenance hormone therapy in patients with metastatic breast cancer

ObjectiveWe investigated the efficacy of maintenance hormone therapy (MHT), which was given to hormone positive metastatic breast cancer (MBC) patients in non-progression status to the previous chemotherapy.MethodsThis study retrospectively analyzed 76 MBC patients who had been treated with MHT from 2006 to 2010 at a single institute.ResultsFor the 76 patients reviewed, the median progression free survival (PFS) to MHT was 14.4 months (95% CI, 11.6–17.3). Prolonged PFS was associated with less previous palliative chemotherapy, fewer metastatic sites, and the absence of visceral metastasis in univariate analysis. Multivariate analysis showed that only the number of previous palliative chemotherapy (HR 1.73, 95% CI, 1.00–2.98; P = 0.04) remained as a significant variable. MHT was generally well tolerated.ConclusionsMHT showed considerable efficacy and tolerability in this study. Further randomized prospective study is warranted.