Summary
Whether hormone replacement therapy (HRT) is beneficial for coronary heart disease (CHD) is controversial. We hypothesized that continuous combined transdermal HRT may have benefits on CHD risk markers without the potential adverse effects seen with certain other HRT regimens. Sixty apparently healthy postmenopausal women, aged 40–65 years, entered a prospective, double‐blind, randomized, placebo‐controlled clinical trial; 55 women completed the 6‐month study. Women received either transdermal oestradiol 17β 0·05 mg and norethisterone acetate 0·125 mg daily, or identical placebo. Circulating markers of vascular function and remodelling, forearm blood flow, lipids and lipoproteins, glucose and insulin, and haemostatic safety parameters were measured at baseline and after treatment. Compared with placebo after 6 months, HRT administration resulted in decreased E‐selectin (P < 0·01), and angiotensin‐converting‐enzyme (ACE; P = 0·05). Cholesterol (P < 0·05), low‐density lipoproteins (LDL; P < 0·05), high‐density lipoprotein3 (HDL3; P < 0·05) and apolipoproteins AII (P < 0·05) and B (P < 0·05), and fasting insulin (P < 0·05) also decreased in the HRT group. Factor VII coagulation activity decreased (P < 0·01) and plasminogen activator inhibitor‐1 and fibrin D‐dimer increased (P < 0·05) in the HRT group, whilst prothrombin fragment 1 + 2 (P < 0·05) decreased, more so in the placebo group. There were no changes in matrix metalloproteinase (MMP)‐2, or in LDL particle size. This transdermal HRT had beneficial effects on vascular function and CHD risk markers.
Postmenopausal hormone therapy with oestradiol plus dydrogesterone can favourably affect lipoprotein concentrations and can reverse menopause-associated changes in insulin secretion and elimination.
c o R R E s P O N D E N c E
Sir,The Editorial in the July issue of the Journal (Vol 103, July 1996) sets up a false dichotomy between pragmatic and explanatory trials. Pragmatic trials aim to see whether an intervention works in the real world rather than the ideal world. The entry criteria are therefore more relevant to the problems clinicians actually face. Explanatory and pragmatic trials have different questions to answer and therefore differ in terms of entry criteria, size and settings. Explanatory trials are useful in exploring the pathophysiology of disease and mechanisms by which an intervention can improve outcome and lead to pragmatic trials. The size of a trial, on the other hand, is relative and trials can only be appropriate or inappropriate size in relation to the question it is attempting to answer. Selection of appropriate research questions and outcome measures should lead to appropriately sized trials. Appropriate interpretation of trial results is also important. A well designed trial may give an equivocal result, either because the intervention has a very small effect, or because of an element of imperfection in the design and conduct of an intervention. At the same time we have to be clear that a negative finding is not an equivocal one. Rarely, if ever, are researchers in a position to predict the effect size with certainty. This is especially the case in pre-eclampsia, where there are many risk factors which may have different weights in different populations and, many unknowns about the pathophysiology of the disease still exist. Almost any biochemical, immunologic marker or measurement done in pre-eclamptic women is found to be abnormal. This is the case with prostacyclin-thromboxane imbalance. It is not easy to know for certain whether an abnormality is a significant contributor to the disease process, in which case interventions that are likely to correct the abnormality might be beneficial, or an epiphenomenon.In summary, we welcome the Editor's plea for more observational and explanatory studies, especially in women with pre-eclampsia. We hope, these will lead to good pragmatic trials designed through shared expertise from different specialties.
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