PAGET'S DISEASE—Changes Occurring Following Treatment with Newer Hormonal Agents

From experience in six cases the anabolic steroid hormones, especially long-acting testosterone and estrogen preparations, are the treatment of choice in Paget''s disease, as in postmenopausal osteoporosis. Details of the management of three patients over a period of four years are presented.Roughly 4 per cent of the population, mostly persons over 40, show some evidence of Paget''s disease. Only a small number of them, however, have severe manifestations requiring treatment, such as pain, howing or fracture of the bones, pressure on nerves or heart failure. In rare cases malignant changes occur in the involved bone.Since the cause of Paget''s disease is not known, treatment in the past has been largely empirical. Reifenstein and Albright had advocated the therapeutic use of calcium, vitamin D and ascorbic acid, and, in postmenopausal women, administration of estrogens; but with fractures or immobilization, intake of calcium-containing foods, such as milk, must be restricted to avoid dangerous piling up of calcium and kidney stones, and fluids must be forced. In recent years anabolic steroid hormones, principally oral androgens and estrogens, have been employed by Gordan and others to promote bone repair, lessen bone pain and decrease urinary excretion of calcium. While these hormones probably do not arrest the disease, they seem to stabilize it and bring relief of symptoms.More recently, Albright and Henneman demonstrated that very large doses of corticotropin (ACTH) or cortisone resulted in immediate cessation of bone pain, decrease in urinary excretion of calcium and histologic evidence of regression of the disease process. The large doses required, however, also produce dangerous side effects, such as psychosis and osteoporosis, indicating that such treatment probably should not be continued over long periods.     

A biomechanical model of Peyronie's disease

Peyronie's disease is a pathological condition of the penis which is characterized by localized ossification of the tunica albuginea. A common symptom of the chronic stage is penile deformity during erection, which is frequently associated with pain and erectile dysfunction. A two-dimensional biomechanical model of the penis was applied to study the development of Peyronie’s disease by simulating the mechanical stress distribution which would result from the interaction of the ossified tunical tissue with other penile soft tissues. The model was solved by using commercial finite element software for a characteristic erectile pressure. The results demonstrate that Peyronie’s plaques may induce intensified stresses around the penile nerves and blood vessels, up to double those in the normal penis. These elevated stresses may cause a painful sensation of neural origin or ischemia in regions of compressed vascular tissue. Severe penile deformities have been shown to develop if Peyronie’s plaques develop only around one of the corpora cavernosa due to the non-homogeneous resistance of the tunica to expansion during erection. The present model can be clinically applied as an aid in the planning process of reconstructive surgery or insertion of a prosthesis.     

Differential influence of peripheral and systemic sex steroids on skeletal muscle quality in pre- and postmenopausal women

Aging is associated with gradual decline of skeletal muscle strength and mass often leading to diminished muscle quality. This phenomenon is known as sarcopenia and affects about 30% of the over 60-year-old population. Androgens act as anabolic agents regulating muscle mass and improving muscle performance. The role of female sex steroids as well as the ability of skeletal muscle tissue to locally produce sex steroids has been less extensively studied. We show that despite the extensive systemic deficit of sex steroid hormones in postmenopausal compared to premenopausal women, the hormone content of skeletal muscle does not follow the same trend. In contrast to the systemic levels, muscle tissue of post- and premenopausal women had similar concentrations of dehydroepiandrosterone and androstenedione, while the concentrations of estradiol and testosterone were significantly higher in muscle of the postmenopausal women. The presence of steroidogenetic enzymes in muscle tissue indicates that the elevated postmenopausal steroid levels in skeletal muscle are because of local steroidogenesis. The circulating sex steroids were associated with better muscle quality while the muscle concentrations reflected the amount of infiltrated fat within muscle tissue. We conclude that systemically delivered and peripherally produced sex steroids have distinct roles in the regulation of neuromuscular characteristics during aging.     

The actions and side effects of Anabolic Steroids in sport and social abuse

Anabolic steroids (AS) derived from testosterone have both anabolic (muscle and strength enhancing) and androgenic (primary and secondary sexual) effects. Efforts to limit the androgenic while enhancing the anabolic effects have not been successful. Alterations to the structure of testosterone, so as to improve the pharmacokinetics of AS, have resulted in drugs, which are orally active, have a longer plasma half life and may be administered as depot injections. Therapeutic doses of AS produce statistically significant effects on strength and athletic performance in well-controlled scientific and clinical trials. At low, therapeutic doses, diet and an intensive training regime are equally important in producing a statistically significant increase in strength. Higher doses 6–7000mg per week are regularly administered in sport and produce the greatest increases in muscle strength erythropoiesis and lean body mass. Patterns of steroid abuse can be complex, reflecting a desire to minimise side effects, and avoid detection. AS side effects are of many types. AS increase salt and water retention leading to an expansion of the blood volume, but effects of steroids on blood pressure are equivocal and most cardiovascular side effects appear to be reversible. Abuse of AS causes an increase in blood triglyceride and cholesterol levels and this is associated with a decline in High Density Lipoproteins (HDLs) and an increase in the Low Density (LDL) type. Though these effects are reversible they are associated with an increased risk of both acute and chronic cardiovascular pathology. The most serious irreversible anabolic steroid side effects are associated with carcinomas-mainly of the liver, prostate and kidney. Hepatic carcinomas are strongly associated with abuse of the orally active 17alpha methyl substituted steroids, which also produce a reversible jaundice. In males, anabolic steroid abuse causes suppression of LH and FSH release leading to inhibition of testosterone production often accompanied by testicular atrophy, and azoospermia. High, chronic doses of the drugs may also cause moderate to severe feminising effects in the form of gynaecomastia. Male secondary sexual characteristics are a side effect of AS abuse in women. Increased insulin resistance and elevated fasting blood glucose levels are the commonest non-gonadal endocrine side effects of AS.     

A novel organogermanium protected atopic dermatitis induced by oxazolone

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that is often associated with other atopic diseases, such as asthma and allergic rhinitis. Although topical steroids have widely been prescribed for patients with AD, skin abnormalities are frequently observed after prolonged steroid treatment. In this study, a novel water-soluble organogermanium compound (Ge-Vit) was prepared because organogermanium is a known INF-γ inducer. The Ge-Vit treatment decreased the basal TEWL and IgE production and attenuated the disruption of the skin barrier function in a murine model of chronic contact dermatitis. The histological examination further supported the anti-AD activities. These results suggested that Ge-Vit can be a useful drug candidate for treating atopic dermatitis.     

Current indications for prevention and therapy of steroid-induced osteoporosis in men and women

Steroid-induced osteoporosis is a textbook example of the secondary type of this medical condition. Glucocorticosteroids suppress bone formation by their direct and indirect effect on osteoblasts, osteoclasts and osteocytes, increasing their resorption and, eventually, leading to negative bone balance. A clinical problem arises regarding the fact that approximately 50% of patients on chronic steroid therapy undergo asymptomatic bone fractures. The treatment mode includes minimising the dose of administered steroids, encouraging an improved lifestyle and supplementation with adequate calcium and vitamin D(3) doses. Bisphosphonates are a group of medical agents used both to prevent and treat steroid-induced osteoporosis, although new therapies have also become available in recent years.     

Current indications for prevention and therapy of steroid-iduced osteoporosis in men and women

Steroid-induced osteoporosis is a textbook example of the secondary type of this medical condition. Glucocorticosteroids suppress bone formation by their direct and indirect effect on osteoblasts, osteoclasts and osteocytes, increasing their resorption and, eventually, leading to negative bone balance. A clinical problem arises regarding the fact that approximately 50% of patients on chronic steroid therapy undergo asymptomatic bone fractures. The treatment mode includes minimising the dose of administered steroids, encouraging an improved lifestyle and supplementation with adequate calcium and vitamin D3 doses. Bisphosphonates are a group of medical agents used both to prevent and treat steroid-induced osteoporosis, although new therapies have also become available in recent years.     

绝经后骨质疏松运动疗法的研究进展

绝经后骨质疏松是一种发生于绝经后妇女的慢性骨代谢疾病,目前其治疗还主要靠药物,但长期使用药物的一些副作用使一些患者不愿意采用药物疗法。因此,其治疗和预防目前仍具有挑战,正日益成为一个公众健康问题。体育运动是防治绝经后骨质疏松的一种非药物疗法,由于其简便、副作用少,近年来备受医患人员的亲睐。本文在查阅国内外相关文献的基础上,对有氧运动、抗阻力运动、平衡和本体感受训练、振动训练和水中训练等不同运动疗法在绝经后骨质疏松防治中的研究进展进行了综述。     

Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study.

OBJECTIVE--To determine the prevalence of continuous use of oral steroids in the general population, the conditions for which they are prescribed, and the extent to which patients taking oral steroids are taking treatment to prevent osteoporosis. DESIGN--A cross sectional study with a four year retrospective review of drug treatment. SETTING--Eight large general practices in central and southern Nottinghamshire. SUBJECTS--A population of 65,786 patients (52% women) registered with a general practitioner during 1995. RESULTS--303 patients (65% (197) women) aged 12-94 years were currently taking "continuous" (for at least three months) oral corticosteroid treatment. This figure represents 0.5% of the total population and 1.4% (245/17 114) of patients aged 55 years or more (1.7% (166/9601) of women). The usual steroid was prednisolone (97% (294/303)), the mean dose was 8.0 mg/day, and the median duration of oral steroid treatment determined in 149 patients was three years. The most common conditions for which continuous oral steroids were prescribed were rheumatoid arthritis (23% (70)), polymyalgia rheumatica (22% (66)), and asthma or chronic obstructive airways disease (19% (59)). Only 41 (14%) of the 303 patients taking oral steroids had received treatment for the prevention of osteoporosis over the past four years. Although 37 of the 41 patients were women, only 10% (18/181) of the women over 45 years taking continuous oral corticosteroids were currently taking hormone replacement therapy. CONCLUSIONS--If our figures are typical then they suggest that over 250,000 people in the United Kingdom are taking continuous oral steroids and that most of these are taking no prophylaxis against osteoporosis.     

Influence of sex steroid hormones on cerebrovascular function.

The cerebral vasculature is a target tissue for sex steroid hormones. Estrogens, androgens, and progestins all influence the function and pathophysiology of the cerebral circulation. Estrogen decreases cerebral vascular tone and increases cerebral blood flow by enhancing endothelial-derived nitric oxide and prostacyclin pathways. Testosterone has opposite effects, increasing cerebral artery tone. Cerebrovascular inflammation is suppressed by estrogen but increased by testosterone and progesterone. Evidence suggests that sex steroids also modulate blood-brain barrier permeability. Estrogen has important protective effects on cerebral endothelial cells by increasing mitochondrial efficiency, decreasing free radical production, promoting cell survival, and stimulating angiogenesis. Although much has been learned regarding hormonal effects on brain blood vessels, most studies involve young, healthy animals. It is becoming apparent that hormonal effects may be modified by aging or disease states such as diabetes. Furthermore, effects of testosterone are complicated because this steroid is also converted to estrogen, systemically and possibly within the vessels themselves. Elucidating the impact of sex steroids on the cerebral vasculature is important for understanding male-female differences in stroke and conditions such as menstrual migraine and preeclampsia-related cerebral edema in pregnancy. Cerebrovascular effects of sex steroids also need to be considered in untangling current controversies regarding consequences of hormone replacement therapies and steroid abuse.     

Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women.

Sex steroid hormones in both males and females have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Evidence also suggests a direct relationship between sex hormones and risk factors for cardiovascular disease. In the present review article, we will discuss recent studies that have examined the complex interrelationships between sex hormones, SHBG, obesity and risk factors for cardiovascular disease. Male obesity and excess abdominal adipose tissue accumulation is associated with reductions in gonadal androgen and low adrenal C19 steroid concentrations. Reduced C19 steroids are also related to an altered metabolic risk factor profile including glucose intolerance and an atherogenic dyslipidemic state. However, the concomitant visceral obese state appears as a major correlate in these associations. In women, menopause-induced estrogen deficiency and increased androgenicity are associated with increased abdominal obesity and with the concomitant alterations in the metabolic risk profile. The accelerated accretion of adipose tissue in the intra-abdominal region coincident with the onset of menopause may explain part of the increased risk of cardiovascular disease in postmenopausal women. In both men and women, plasma levels of sex hormone-binding globulin are strong correlates of obesity and risk factors for cardiovascular disease, and more importantly, the relationships between low SHBG and altered plasma lipid levels appear to be independent from the concomitant increased levels of visceral adipose tissue. SHBG concentration may, therefore, represent the most important and reliable marker of the sex hormone profile in the examination of the complex interrelation of sex steroid hormones, obesity, and cardiovascular disease risk.     

Age-associated Iron Accumulation in Bone: Implications for Postmenopausal Osteoporosis and a New Target for Prevention and Treatment by Chelation

Iron accumulation in tissues is believed to be a characteristic of aged humans and a risk factor for some chronic diseases. However, it is not known whether age-associated iron accumulation is part of the pathogenesis of postmenopausal osteoporosis that affects approximately one out three women worldwide. Here, we confirmed that this accumulation of iron was associated with osteopenia in ovariectomized (OVX) rats (a model of peri- and postmenopausal osteoporosis due to estrogen deficiency). To further investigate whether the increased iron level plays a causal role in the onset of bone loss, we treated OVX rats with an orally active and bone targeted chelator that prevented iron accumulation in their skeletal tissues. The results showed that this treatment mitigated the loss of bone mass and the deterioration of bone micro-architecture. We also found that one possible mechanism of the protective action of iron chelation was to significantly reduce bone resorption. Thus, these findings provide a novel target and a potentially useful therapeutic strategy for the prevention and treatment of postmenopausal osteoporosis and perhaps other age-related diseases.     

Sex steroids, glucocorticoids, stress and autoimmunity

Interest in the field of neuroimmunoendocrinology is in full expansion. With regard to this, steroid influence on the immune system, in particular sex steroids and glucocorticoids, has been known for a long time. Sex steroids are part of the mechanism underlying the immune sexual dimorphism, as particularly emphasized in autoimmune diseases. Immunosuppressive and anti-inflammatory effects of glucocorticoids are now considered a physiological negative feedback loop to cytokines produced during an immune and/or inflammatory response. Psychosocial factors may play a role in the development of immunologically-mediated diseases, e.g. autoimmune diseases. The nonobese diabetic (NOD) mouse, that develops an immunologically-mediated insulin-dependent diabetes mellitus (IDDM) is an interesting model to study the role of endogenous steroids. Insulitis is present in both sexes, but diabetes has a strong preponderance in females. Hormonal alteration, such as castration, modulates the incidence of diabetes, whereas environmental factors, such as stress, accelerate the disease. In the present paper, we have reviewed the role of gender, sex steroid hormones, stress and glucocorticoids in autoimmunity as well as analyzed their different levels of actions and interrelationships, focusing particular attention on the immunologically-mediated IDDM of the NOD mouse.     

The significance of steroid metabolism in human cancer

Epidemiological and clinical evidence suggests that steroid hormones are intimately involved in the natural history of many cancers, including those of the breast, endometrium and prostate. However, it has been difficult to demonstrate that progressive changes in tumour development are related to circulating levels of steroids. This may be because further metabolism of steroids occurs locally within the tumour and its adjacent host tissue. Using the breast as an example, data has been reviewed that such local metabolism may (a) markedly change the biological potency of steroid hormones and (b) be associated with the risk, presence, pathology, stage and hormone sensitivity of cancer. The implications of these findings are discussed including the need to identify factors which regulate steroid metabolism in peripheral tissue and tumours. In this way the potential to influence the microenvironment around and within tumour cells may be realized in favour of the patient.     

Sex steroid hormones enhance hypotensive effects of calcitonin gene-related Peptide in aged female rats

The aim of the present study is to investigate whether vascular protective effects of steroid hormones in aged female rats are mediated through calcitonin gene-related peptide (CGRP), a known potent vasodilator. This rat model reflects the postmenopausal state in humans. We examined whether blood pressure lowering effects of CGRP are enhanced in aged female rats when steroid hormone treatments are administered. We observed that 1) continuous infusion of CGRP lowered blood pressures in rats treated with estradiol-17beta and progesterone (P < 0.05), 2) acute hypotensive effects of CGRP were significantly (P < 0.05) greater in the presence of steroid hormones than in vehicle-treated groups, 3) blood pressure decreases in response to CGRP are lower in aged female rats than they are in young adult ovariectomized rats, and 4) age-related differences in the hypotensive effects of CGRP were nullified when animals were treated with steroid hormones. These data suggest that female sex steroid hormones may modulate arterial blood pressure by regulating the CGRP effector system in female rats regardless of age.     

Leptin and its receptor are controlled by 17beta-estradiol in peripheral tissues of ovariectomized rats

It has been widely shown that there is a complex interaction between sex steroids and leptin effects on body weight. In this sense, the absence of female sex steroids is linked to a significant increase in body weight, which seems to be related to an impairment of the central actions of leptin. The present study was designed to elucidate the effects of two different treatments with 17beta-estradiol on leptin receptor and serum leptin levels in ovariectomized rats, a model of postmenopausal condition. Our results have shown that plasma leptin levels in ovariectomized rats were lower than in estradiol-treated animals, thereby supporting a positive effect of this steroid. Recent information has extended leptin actions to peripheral tissues, mainly to insulin-dependent tissues, this effect being related to metabolic actions. To better understand the peripheral effects of leptin and their possible regulation by estradiol treatment, we have analyzed leptin receptor expression in the skeletal muscle and the adipose tissue. Our results showed a tissue-specific regulation of this protein: Ob-Rb expression in the adipose tissue decreased when the time of treatment or the dose of estradiol administered increased, suggesting less sensitivity to leptin in this tissue, whereas in the skeletal muscle the changes in this protein followed the same profile as the plasma leptin levels. We think that this specific regulation could ensure a different response of each tissue toward the same serum leptin level. Further studies to clarify this situation are ongoing.     

Fatty acid esters of steroids: synthesis and metabolism in lipoproteins and adipose tissue

At the end of the last century ideas concerning the physiological role of the steroid fatty acid ester family were emerging. Estrogens, fatty acylated at C-17 hydroxyl group and incorporated in lipoproteins were proposed to provide antioxidative protection to these particles. A large number of studies involving non-estrogenic adrenal steroids, and their fatty acylated forms, demonstrated their lipoprotein-mediated transport into cells and subsequent intracellular activation, suggesting a novel transport mechanism for lipophilic steroid derivatives. After these important advances the main focus of interest has shifted away from C-19 and C-21 steroids to fatty acylated estrogens. However, interest in their lipoprotein-mediated transport has decreased because only minute amounts of these derivatives were detected in circulating lipoproteins, and their antioxidative activity remained unconfirmed under physiological circumstances. It now appears that the overwhelming majority of estradiol in postmenopausal women resides in adipose tissue, most of it in esterified form. This is poorly reflected in plasma levels which are very low. Recent data suggest that estrogen fatty acid esters probably represent a storage form. The future focus of investigation is likely to be on firstly, the enzymatic mechanisms regulating the esterification and de-esterification of estradiol and other steroids residing in adipose tissue and secondly, on the role of insulin and other hormones in the regulation of these enzymatic mechanisms. Thirdly, as a large proportion of fatty acid esterified C-19 and C-21 non-estrogenic steroids is transported in lipoproteins and as they are important precursors of androgens and estrogens, this field should be investigated further.     

Steroid catabolism in marine and freshwater fish

Steroids play important roles in regulating many physiological functions in marine and freshwater fish. Levels of active steroid in blood and tissues are determined by the balance between synthetic and catabolic processes. This review examines what is known about pathways of catabolism of steroids, primarily sex steroids, in marine and freshwater fish. Cytochrome P450 (P450) isoforms present in hepatic microsomes catalyze steroid hydroxylation to metabolites with lower or no activity at estrogen or androgen receptors. Important pathways of steroid catabolism to readily excreted metabolites are glucuronidation and sulfonation of hydroxyl groups. Estradiol, testosterone, DHEA and hydroxylated metabolites of these and other steroids readily form glucuronide and sulfate conjugates in those fish species where these pathways have been examined. Little is known, however, of the structure and function of the UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes involved in steroid conjugation in fish. Glucuronide and sulfate conjugates of steroids may be transported into and out of cells by organic anion transporter proteins and multi-drug resistance proteins, and there is growing evidence that these proteins play important roles in steroid conjugate transport and elimination. Induction or inhibition of any of these pathways by environmental chemicals can result in alteration of the natural balance of steroid hormones and could lead to disruption of the endocrine system. Recent studies in this area are presented, with particular focus on phase II (conjugative) pathways.     

Oxidative stress contributes to chronic leg vasoconstriction in estrogen-deficient postmenopausal women.

Basal whole leg blood flow and vascular conductance are reduced in estrogen-deficient postmenopausal compared with premenopausal women. The underlying mechanisms are unknown, but oxidative stress could be involved. We studied 9 premenopausal [23 +/- 1 yr (mean +/- SE)] and 20 estrogen-deficient postmenopausal (55 +/- 1 yr) healthy women. During baseline control, oxidized low-density lipoprotein (LDL), a marker of oxidative stress, was 50% greater in the postmenopausal women (P < 0.001). Basal whole leg blood flow (duplex ultrasound of femoral artery) was 34% lower in the postmenopausal women because of a 38% lower leg vascular conductance (P < 0.0001); mean arterial pressure was not different. Intravenous administration of a supraphysiological dose of the antioxidant ascorbic acid increased leg blood flow by 15% in the postmenopausal women as a result of an increase in leg vascular conductance (both P < 0.001), but it did not affect leg blood flow in premenopausal controls or mean arterial pressure in either group. In the pooled subjects, the changes in leg blood flow and leg vascular conductance with ascorbic acid were related to baseline plasma oxidized LDL (r = 0.46 and 0.53, P < 0.01) and waist-to-hip ratio and total body fat (r = 0.41-0.44, all P < 0.05). Our results are consistent with the hypothesis that oxidative stress contributes to chronic leg vasoconstriction and reduced basal whole leg blood flow in estrogen-deficient postmenopausal women. This oxidative stress-related suppression of leg vascular conductance and blood flow may be linked in part to increased total and abdominal adiposity.