Hormone replacement therapy with dydrogesterone and 17β-oestradiol: effects on serum lipoproteins and glucose tolerance during 24 month follow up

Objective To assess serum lipid and lipoprotein concentrations and oral glucose tolerance in postmenopausal women treated with 17β-oestradiol (2 mg/day) and cyclical dydrogesterone (10 mg/day for 14 days per 28 day cycle).
Design A 24 month prospective study of 29 women acting as their own controls. On-treatment samples were taken during the combined (oestrogen–progestogen) phase of therapy.
Setting Metabolic research unit in London.
Population Postmenopausal women with no previous exposure to hormone replacement therapy attending a menopause clinic in a London hospital.
Methods Fasting serum sampling and oral glucose tolerance testing.
Main outcome measures Serum lipids and lipoprotein concentrations and plasma glucose, insulin and C-peptide responses to an oral glucose load.
Results Restricting the analysis to the 17 women who completed the study, no effect was seen on serum triglyceride concentrations. There was a mean fall of 5.9% (95% CI 1.2 to −13.0) in concentrations of serum total cholesterol, reflecting the balance of a 10.7% fall (95% CI 4.3 to −25.8) in low density lipoprotein cholesterol concentrations and a 16.3% increase (95% CI 7.3 to −25.3) in those of high density lipoproteins. Fasting glucose concentrations and glucose tolerance test responses were unchanged. Fasting insulin concentrations fell substantially (–41.6%, 95% CI −23.4 to −59.8) with falls also being seen in insulin responses to glucose. Fasting C-peptide concentrations increased by 36.2% (95% CI 9.17 to 63.3), with no consistent effect on C-peptide responses to glucose.
Conclusions Dydrogesterone did not appear to oppose the potentially beneficial effects of oestradiol on insulin or either low or high density lipoproteins, making the combination with 17β-oestradiol a potentially useful option for postmenopausal women particularly those at risk of cardiovascular disease or diabetes mellitus.     

The metabolic consequences of treating postmenopausal women with non-oral hormone replacement therapy

Objective To define the metabolic profile of postmenopausal hormone replacement therapies when delivered through gels, patches, implants or other non-oral routes. Such information may be useful in the absence of reliable clinical data on the effects of these therapies on the risk of cardiovascular disease.
Design and methods Selective literature review.
Patients Postmenopausal women.
Results Non-oral oestrogen therapies fail to invoke the hepatic response associated with oral therapy. Changes in hepatic protein synthesis are minimal and so plasma levels of binding globulins and other proteins tend to be normal. Many of the perturbations of the haemostatic system seen with oral therapy are avoided. In the absence of hepatic over-synthesis of apolipoproteins, plasma lipoprotein levels are unchanged or reduced. The direct effects of oestrogen on vascular function are apparent when the hormone is administered non-orally.
Conclusions The net effect of non-oral oestrogen therapies on the risk of cardiovascular disease is difficult to predict on the basis of current data. Some changes in plasma lipoprotein levels, such as the reduced fasting levels of triglycerides, would be considered desirable, but the cardioprotective increase in levels of high-density lipoproteins is absent. The differential effect on haemostasis markers is promising, but preliminary data relating to transdermal patches fail to support the idea that non-oral therapies will avoid the increased risk of venous thromboembolism associated with oral therapy. The ability of non-oral therapies to improve vascular function implies that they will offer postmenopausal women at least some of the cardiovascular protection seen with oral therapy.     

Dosimetric methods in the optimization of radiotherapy for carcinoma of the uterine cervix

Pelvic failures and late radiation sequelae were analyzed using the dosimetric parameters of ICRU Report 38 for 338 patients with Stage I-III carcinoma of the uterine cervix treated by radiation alone and followed for a minimum of 2 years. The pelvic recurrence rates were: Stage IB 5.1% (N = 118, 1% pelvis alone), Stage IIA 15.1% (N = 53, 9.4% pelvis alone), Stage IIB 15.8% (N = 76, 9.2% pelvis alone) and Stage IIIB 28.9% (N = 76, 17.1% pelvis alone). For Stages I and II pelvic failure was unrelated to cumulated lateral parametrial dose (CDPW) or reference volumes, but for Stage IIIB was higher for CDPW above 65 Gy. Overall complication rates were: grade 3-10.1% and grade 2-18.1% but were much lower for 176 patients treated with stem and ovoids (S + O: grade 3-5.7%, grade 2-15.7%) than for 43 receiving vaginal cylinders (grade 3-37.2%, grade 2-28%). Grade 3 rectal complications associated with cylinders were related to a maximal vaginal application over 1.50 cGy X m2 of total reference air kerma (or 2080 mgh) and cumulated rectal reference doses (CDRref) above 75 Gy. For the S + O group, grade 2 and 3 rectal complications increased with increasing reference volumes (hwt and HWT) and showed dose thresholds for CDRref and CDRmean (grade 3: 75 Gy). Prospective use of zones of risk defined graphically on a dose-volume plot (CDRref vs HWT) has reduced our severe complication rate without reducing local control. This technique requires individualization of patient therapy, rapid access to computerized dosimetry and the establishment of center- and applicator-specific risks of complications.     

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear. In this study, we used a renal bilateral ischemia-reperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b⁺ cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies. Macrophage populations were isolated from kidney homogenates by fluorescence-activated cell sorting for whole genome microarray analysis. The CD11b⁺/Ly6C^high population associated with the onset of renal injury and increase in proinflammatory cytokines, whereas the CD11b⁺/Ly6C^intermediate population peaked during kidney repair. The CD11b⁺/Ly6C^low population emerged with developing renal fibrosis. Principal component and hierarchical cluster analyses identified gene signatures unique to each population. The CD11b⁺/Ly6C^intermediate population had a distinct phenotype of wound healing, confirmed by results of studies inhibiting the macrophage colony-stimulating factor 1 receptor,whereas the CD11b⁺/Ly6C^low population had a profibrotic phenotype. All populations, including the CD11b⁺/Ly6C^high population, carried differential inflammatory signatures. The expression of M2-specific markers was detected in both the CD11b⁺/Ly6C^intermediate and CD11b⁺/Ly6C^low populations, suggesting these in vivo populations do not fit into the traditional classifications defined by in vitro systems. Results of this study in a renal ischemia-reperfusion injury model allow phenotype and function to be assigned to CD11b⁺/Ly6C⁺ monocyte/macrophage populations in the pathophysiology of disease after AKI.