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Given the rapidly increasing number of women above 50 it is of pivotal importance to consider health issues related to gonadal hormone deficiency. The possibility of alleviating such symptoms by hormone replacement therapy (HRT) should be recognized by all physicians, not merely by gynaecologists. But which women should be given what therapy, and for how long? Due to the increased risk of endometrial cancer and bleeding problems when using oestrogen monotherapy, only women who have undergone hysterectomy could use this regimen unless treatment is aimed at amelioration of urogenital symptomatology only. In this case a vaginal administration of low-dose oestrogens is possible as such doses do not induce endometrial proliferation. In all other cases a combination of an oestrogen and a progestogen must be used. There are several options for doing so. During the early phase of the climacteric period when irregular and/or heavy vaginal bleeds are part of the symptomatology a cyclical therapy will often combat these problems. As women pass into the menopause a sequential regimen is often preferred until 1-3 years have elapsed since menopause. With advancing time since menopause women become more and more reluctant to experience monthly bleeds. In such cases a continuous combined regimen may be offered even though it cannot guarantee a bleed-free remedy.Non-oral, particularly transdermal, therapy is an alternative in women with co-existing morbidity such as migraine, diabetes, malfunction of the gastrointestinal tract and liver disease. Oral therapy is preferred particularly in women with elevated plasma levels of LDL-cholesterol, lipoprotein(a) or homocysteine. Oral therapy induces liver protein synthesis. This could be an advantage in cases with low plasma levels of sex hormone-binding globulin (SHBG) as low levels of SHBG may promote androgenic stigmata such as hirsutism and a lowering of the voice. However, in cases with too low an androgen influence the use of a non-oral therapy may counteract symtoms such as low libido.Tibolone could be used for the prevention (and treatment?) of osteoporosis but it will also mitigate the typical climacteric symptoms. Raloxifene is a fairly new type of drug which is classified as a selective oestrogen receptor modulator (SERM). It will reduce vertebral fractures to the same extent as bisphosphonates, albeit the increase in bone density is less. Raloxifene has no effect on climacteric symptoms. Its greatest benefit is a clear reduction of breast cancer in women, which is in contrast to HRT/ERT.There are insufficent data on tibolone and the incidence of breast cancer. Experimental data, however, are intriguing in suggesting less impact on the breast than conventional HRT/ERT.
Best Pract Res Clin Obstet Gynaecol 2002 Jun
PMID:The role of ERT/HRT. 1209 68

Peripheral arterial disease (PAD) is associated with a high morbidity and mortality, largely from coronary and cerebrovascular disease, which often overshadows the PAD itself. Best Medical Therapy (BMT), comprising smoking cessation, antiplatelet agent use, cholesterol reduction, exercise therapy, and the diagnosis and treatment of hypertension and diabetes mellitus; is evidenced based and can result in significant reductions in cardiovascular risk, as well as some improvement in PAD. Previous data have largely been restricted to patients with coronary artery disease, and their relevance to PAD has been extrapolated. However, data are now starting to become available, such as the Heart Protection Study, with data specific to PAD patients. This article reviews the data regarding the use of BMT in patients with PAD, and based on this, makes recommendations for the use of BMT in this group of patients.
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PMID:What constitutes best medical therapy for peripheral arterial disease? 1262 55

In the 21st century, patients suffering from diabetes mellitus (DM), a lifestyle-related disease, will increase more than in the 20th century. DM is threatening because of the development of many severe secondary complications, including atherosclerosis, microangiopathy, renal dysfunction and failure, cardiac abnormalities, diabetic retinopathy, and ocular disorders. Generally, DM is classified as either insulin-dependent type 1 or noninsulin-dependent type 2 DM. Type 1 DM is treated only by daily insulin injections; type 2 DM is treated by several types of synthetic therapeutic substances together with a controlled diet and physical exercise. Even with these measures, the daily necessity for several insulin injections can be painful both physically and mentally, whereas the synthetic therapeutic substances used over the long term often have side effects. For those reasons, the creation and development of a new class of pharmaceuticals for treatment of DM in the 21st century would be extremely desirable. In the last half of the 20th century, investigations of the relationships among diseases and micronutrients, such as iron, copper, zinc, and selenium, have been numerous. Research into the development of metallopharmaceuticals involving the platinum-containing anticancer drug, cisplatin, and the gold-containing rheumatoid arthritis drug, auranofin, has also been widespread. Such important findings prompted us to develop therapeutic reagents based on a new concept to replace either insulin injections or the use of synthetic drugs. After many trials, we noticed that vanadium might be very useful in the treatment of DM. Before the discovery of insulin by Banting and Best in 1921 and its clinical trial for treating DM, the findings in 1899, in which orally administered sodium vanadate (NaVO(3)) was reported to improve human DM, gave us the idea to use vanadium to treat DM. However, it has taken a long time to obtain a scientific explanation as to why the metal ion exhibits insulin-mimetic or blood-glucose lowering effects in in vitro and in vivo experiments. After investigations from many perspectives involving biochemistry and bioinorganic chemistry, vanadyl sulfate (VOSO(4)) and its complexes with several types of ligands have been proposed as useful for treating DM in experimental diabetic animals. On the basis of a mechanistic study, this article reports on recent progress regarding the development of antidiabetic vanadyl complexes, emphasizing that the vanadyl ion and its complexes are effective not only in treating or relieving both types of DM but also in preventing the onset of DM.
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PMID:A new concept: the use of vanadium complexes in the treatment of diabetes mellitus. 1220 6

Iron deficiency is the most common disorder of iron metabolism worldwide, but there is concern that iron accumulation resulting from enhanced iron absorption may also be a cause of morbidity. In patients with genetic haemochromatosis the clinical manifestations of iron overload are well-known. In northern Europe 90% of such patients are homozygous for the C282Y mutation of the HFE gene and this genotype is found in 1 in 200 of the population. Heterozygosity for C282Y occurs in 15% of the population and 25% carry another mutation, H63D. Population studies have revealed (i) the serum transferrin saturation is strongly influenced by HFE genotype, being lowest in subjects lacking mutations and highest in those homozygous for C282Y; (ii) most subjects homozygous for C282Y accumulate iron but do not present with the clinical manifestations of iron overload. Testing for HFE mutations in clinics for diabetes, liver disease and cardiovascular disease has shown that homozygosity for C282Y is not commonly found. Heterozygosity for either C282Y or H63D does not appear to be a risk factor for these common conditions.
Best Pract Res Clin Haematol 2002 Jun
PMID:HFE Mutations as risk factors in disease. 1240 9

Iron overload in body tissues can cause complications such as cirrhosis, cardiomyopathy, diabetes, hypogonadism and arthritis. In populations of northern European descent, most iron overload is due to hereditary haemochromatosis (HHC), a genetic condition that causes increased iron absorption. HHC can be treated or prevented by regular phlebotomy treatments. Some experts have called for population screening for HHC, so that early phlebotomy treatment can be initiated. Two screening tests are available: measurement of the serum iron transferrin saturation (Tf%) and genetic testing for HFE mutations. However, both methods have low positive predictive values. Current data suggest that most people at risk are unlikely to develop clinical symptoms and that the population prevalence of clinical complications of HHC is low, arguing against population screening. Two other prevention strategies are available. (1) Health provider education, to heighten awareness of HHC as an explanation for symptoms and signs seen in early iron overload including unexplained fatigue, joint pain, palpitations, abdominal pain, elevated liver function tests, hepatomegaly and elevated serum ferritin. (2) Family-based testing after a diagnosis of HHC, to ensure that relatives are evaluated for evidence of iron overload. More research is also needed to identify the factors that increase risk for disease in persons with excess iron uptake, to determine whether moderate iron overload is a health risk and to evaluate the causes of iron overload other than HHC.
Best Pract Res Clin Haematol 2002 Jun
PMID:Hereditary haemochromatosis: a realistic approach to prevention of iron overload disease in the population. 1240 10

Nonalcoholic steatohepatitis (NASH), which is the most severe histological form of nonalcoholic fatty liver disease (NAFLD), is emerging as the most common clinically important form of liver disease in developed countries. Although its prevalence is 3% in the general population, this increases to 20-40% in obese patients. Since NASH is associated with obesity, prevalence has been predicted to increase along with the arsent epidemic of obesity and type II diabetes mellitus. The importance of this observation comes from the fact that NASH is a progressive fibrotic disease, in which cirrhosis and liver-related death occur in 25% and 10% in these patients respectively over a 10-year period. This is of particular concern given the increasing recognition of NASH in children. Treatment consists of treating obesity and its co-morbidities; diabetes and hyperlipidemia. Nascent studies suggest that a number of pharmacological therapies may be effective, but all remain unproven at present. Histological and laboratory improvement occurs with a 10% decrease in body weight. Bariatric surgery is indicated in selected patients.A greater understanding of the pathophysiological progression of NASH in obese patients must be obtained in order to develop more focused and improved therapy.
Best Pract Res Clin Gastroenterol 2002 Oct
PMID:Steatohepatitis in obese individuals. 1240 42

Non-alcoholic fatty liver disease (NAFLD) is usually seen in middle-aged women with obesity, non-insulin-dependent diabetes mellitus and/or hyperlipidaemia. NAFLD has also been associated with other conditions. Surgical procedures to treat obesity such as jejunoileal bypass and gastroplasty as well as massive small bowel resection have been associated with NAFLD. Mechanisms such as rapid weight loss, certain nutritional deficiencies and bacterial overgrowth have been proposed. Other nutritional conditions such as extreme malnutrition and total parenteral nutrition can also cause NASH. This can be due to abnormal glucose and fat metabolism, deficiencies like carnitine, essential fatty acid and choline or, in the case of parenteral nutrition, excess of calories, glucose or lipids. Several drugs have also been implicated as well as some inborn errors of metabolism and, more rarely, other diseases.
Best Pract Res Clin Gastroenterol 2002 Oct
PMID:Other disease associations with non-alcoholic fatty liver disease (NAFLD). 1240 45

Treatment of patients with non-alcoholic steatohepatitis (NASH) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. NASH associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate control of glucose and lipid levels is always recommended, but is not always effective in reversing the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, alpha-tocopherol, metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit for patients with NASH. These medications, however, need first to be tested in well-controlled trials with clinically relevant end-points and extended follow-up. A better understanding of the pathogenesis and natural history of NASH will help to identify the subset of patients at risk of progressing to advanced liver disease and, hence, those patients who should derive the most benefit from medical therapy.
Best Pract Res Clin Gastroenterol 2002 Oct
PMID:Treatment of non-alcoholic steatohepatitis. 1240 46

During the first two decades of the 20th century, several investigators prepared extracts of pancreas that were often successful in lowering blood sugar and reducing glycosuria in test animals. However, they were unable to remove impurities, and toxic reactions prevented its use in humans with diabetes. In the spring of 1921, Frederick G. Banting, a young Ontario orthopedic surgeon, was given laboratory space by J.J.R. Macleod, the head of physiology at the University of Toronto, to investigate the function of the pancreatic islets. A student assistant, Charles Best, and an allotment of dogs were provided to test Banting's hypothesis that ligation of the pancreatic ducts before extraction of the pancreas, destroys the enzyme-secreting parts, whereas the islets of Langerhans, which were believed to produce an internal secretion regulating sugar metabolism, remained intact. He believed that earlier failures were attributable to the destructive action of trypsin. The name "insuline" had been introduced in 1909 for this hypothetic substance. Their experiments produced an extract of pancreas that reduced the hyperglycemia and glycosuria in dogs made diabetic by the removal of their pancreases. They next developed a procedure for extraction from the entire pancreas without the need for duct ligation. This extract, now made from whole beef pancreas, was successful for treating humans with diabetes. Facilitating their success was a development in clinical chemistry that allowed blood sugar to be frequently and accurately determined in small volumes of blood. Success with purification was largely the work of J.B. Collip. Yield and standardization were improved by cooperation with Eli Lilly and Company. When the Nobel Prize was awarded to Banting and Macleod for the discovery of insulin, it aggravated the contentious relationship that had developed between them during the course of the investigation. Banting was outraged that Macleod and not Best had been selected, and he briefly threatened to refuse the award. He immediately announced that he was giving one-half of his share of the prize money to Best and publicly acknowledged Best's contribution to the discovery of insulin. Macleod followed suit and gave one-half of his money award to Collip. Years later, the official history of the Nobel Committee admitted that Best should have been awarded a share of the prize.
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PMID:Insulin: discovery and controversy. 1244 92

The insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP proteases are the main regulators of somatic growth and cellular proliferation. IGFs are involved in growth pre-natally and post-natally. Dysregulation of the IGF axis can lead to growth disorders such as growth hormone deficiency and acromegaly. Pre-natally, this dysregulation can lead to IUGR or macrosomia. IGFs also have an important mitogenic action and play a role in tumorigenesis and cancer. These actions are regulated by co-interactions with IGFBPs, especially IGFBP-3. In addition to somatic growth and mitogenic activity, IGFs have hypoglycaemic and insulin sensitizing actions, and their dysregulation is involved in diabetes and its complications. In this chapter, we examine the role of IGFs and IGFBPs in growth, tumorigenesis and diabetes, and discuss treatment modalities for each disease involving the GH-IGF-IGFBP axis, including discussion of current in vitro and in vivo investigations in this field.
Best Pract Res Clin Endocrinol Metab 2002 Sep
PMID:IGFs and IGFBPs: role in health and disease. 1246 27


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