Showing papers in "Baillière's clinical endocrinology and metabolism in 1998"
TL;DR: This chapter presents a review of studies on staple plant foods, indicating that plants contain, besides a wide range of chemicals with a number of biological properties, biologically active phytoestrogens--precursors of hormone-like compounds found in mammalian systems.
Abstract: Plants abound in essential phytochemicals produced for their various vital functions. The same compounds seem also to be crucial for human health and disease. Recent human epidemiological and laboratory animal and cell studies on cancer and heart disease have highlighted the phytoestrogens--naturally occurring principles that share with steroidal oestrogens an ability to activate oestrogen receptors. The best known non-steroidal phytoestrogens include the isoflavones daidzein, genistein, formononetin and biochanin A, the coumestan coumestrol, and the lignans secoisolariciresinol and matairesinol. Acknowledging the potentially chemoprotective role of these non-nutrients, we have quantified all biologically important isoflavonoids and lignans in cereals, oilseeds and nuts, legumes, vegetables, fruits, berries and beverages such as tea, coffee and wine. In this chapter, we present a review of our studies on staple plant foods, indicating that plants contain, besides a wide range of chemicals with a number of biological properties, biologically active phytoestrogens--precursors of hormone-like compounds found in mammalian systems.
303 citations
TL;DR: It is revealed that high levels of lignans and isoflavonoids are frequently associated with low breast, prostate and colon cancer risk, as well as a low risk of coronary heart disease, and these compounds seem to be cancer protective and/or are biomarkers of a ‘healthy’ diet.
Abstract: Epidemiological studies have revealed that high levels of lignans and isoflavonoids are frequently associated with low breast, prostate and colon cancer risk, as well as a low risk of coronary heart disease. These compounds seem to be cancer protective and/or are biomarkers of a ‘healthy’ diet. All soy protein products consumed by Asian populations have high concentrations of isoflavonoids. In other countries, such as Finland and Sweden, the lignan levels are higher in populations with the lowest risk because of a high consumption of whole-grain rye bread, berries and some vegetables. There is a strong association between fibre intake per kilogram body weight and lignan concentrations in body fluids. Breast cancer has been found to be associated with low lignan levels in the USA, Finland, Sweden and Australia. With regard to prostate and colon cancer, as well as coronary heart disease, the epidemiological data related to phytoestrogens are still very limited.
212 citations
TL;DR: The only positive effects of phytoestrogens on bone observed so far in post-menopausal women have been small and limited to the lumbar vertebrae.
Abstract: Practically all plant foods contain small amounts of the diverse phytoestrogen moleculesthat have the potential to improve health. Phytoestrogens, especially the soy-derived isoflavones, are receiving great scrutiny as food supplements for the purposes of both enhancing the health of tissues and preventing several common diseases, such as cardiovascular diseases, cancers of reproductive tissues and osteoporosis. Investigations of isoflavones, in particular, have recently become more prominent because of their oestrogenic activities. These actions may be as either partial oestrogen agonists or antioestrogens (inhibitors of natural oestrogen activity). For example, the isoflavones of soy, mainly genistein and daidzein, have been shown by at least three different laboratories to conserve bone in ovariectomized rodent models, and they probably have similar conservatory effects in higher mammalian species. Nevertheless, the only positive effects of phytoestrogens on bone observed so far in post-menopausal women have been small and limited to the lumbar vertebrae. Additional information on human studies currently in progress is needed before the efficacy of these preparations in human subjects is known.
138 citations
TL;DR: The emerging adverse trends in human reproductive health, such as increased incidences of cryptorchidism, hypospadias and testicular cancer, and the ubiquitous presence of endocrine disrupters in the environment, support the hypothesis that disturbed sexual differentiation could in some cases be caused by increased exposure to environmental endocrinedisrupters.
Abstract: Male sexual differentiation is dependent on normal testicular function, including secretion of testosterone from the Leydig cells, and mullerian-inhibiting substance from the Sertoli cells. External factors, such as anti-androgens and oestrogens, that disturb endocrine balance cause demasculinizing and feminizing effects in the developing male fetus. Oestrogens also causes adverse effects in female fetuses, whereas anti-androgens have little influence. A growing number of chemicals have been found to possess either weak oestrogenic, anti-androgenic or other hormonal activities, and these are often referred to as endocrine disrupters. In animals in the wild, abnormal sexual development has been associated with exposure to mixtures of endocrine disrupters. The emerging adverse trends in human reproductive health, such as increased incidences of cryptorchidism, hypospadias and testicular cancer, and the ubiquitous presence of endocrine disrupters in the environment, support the hypothesis that disturbed sexual differentiation could in some cases be caused by increased exposure to environmental endocrine disrupters.
136 citations
TL;DR: This paper reviews the experimental studies in animals and humans demonstrating the anti-cancer effects of flaxseed and its SDG as well as other studies relevant to the clinical use of lignans, such as those on their food sources, bio-availability and safety.
Abstract: Mammalian lignans are produced from plant precursors such as secoisolariciresinol diglycoside (SDG) and matairesinol via the action of bacteria in the human or animal colon. While precursors are found in many plant foods, flaxseed is the richest source of SDG and was therefore used as a model to determine the anti-cancer effects of lignans. This paper reviews the experimental studies in animals and humans demonstrating the anti-cancer effects of flaxseed and its SDG as well as other studies relevant to the clinical use of lignans, such as those on their food sources, bio-availability and safety.
123 citations
TL;DR: The wide distribution of isoflavonoids and flavonoids in the plant kingdom, together with their anti-angiogenic and anti-mitotic properties, suggest that these phytoestrogens may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumours.
Abstract: The consumption of a plant-based diet can prevent the development and progression of chronic diseases associated with extensive neovascularization, including the progression and growth of solid malignant tumours. We have previously shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell proliferation and in vitro angiogenesis. Moreover, the concentration of genistein in the urine of subjects consuming a plant-based diet is 30-fold higher than that in subjects consuming a traditional Western diet. We have also reported that certain structurally related flavonoids are more potent inhibitors than genistein. Indeed, 3-hydroxyflavone, 3',4'-dihydroxyflavone, 2',3'-dihydroxyflavone, fisetin, apigenin and luteolin inhibit the proliferation of normal and tumour cells as well as in vitro angiogenesis at half-maximal concentrations in the lower micromolar range. The wide distribution of isoflavonoids and flavonoids in the plant kingdom, together with their anti-angiogenic and anti-mitotic properties, suggest that these phytoestrogens may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumours.
123 citations
TL;DR: Soy foods and soybean components have received considerable attention of late for their potential role in reducing cancer risk, but there is, at the moment, very limited support for soy exerting a protective effect against this type of cancer.
Abstract: Soy foods and soybean components have received considerable attention of late for theirpotential role in reducing cancer risk. Although the relationship between soy intake and the risk of breast and prostate cancer has been the focus of most interest, the relationship between soy intake and other cancers, including colorectal cancer, has also been studied. Several anti-carcinogens have been identified in soybeans, but most enthusiasm for the potential anti-cancer effects of soy undoubtedly stems from work involving soybean isoflavones. Isoflavones have a limited distribution in nature, and, for practical purposes, soyfoods are the only nutritionally relevant dietary source of these phytochemicals. Isoflavones are weak oestrogens but possess other potentially important biological attributes independent of their ability to bind to the oestrogen receptor. The isoflavone genistein inhibits the growth of most types of hormone-dependent and hormone-independent cancer cells in vitro, including colonic cancer cells. Several mechanisms for the in vitro anti-cancer effects of genistein have been proposed, including effects on signal transduction. A number of epidemiological studies, primarily of Asian origin, have examined the relationship between soy intake and the risk of colorectal cancer. Although these studies provide little support for a protective effect of soy, concerns have been raised about the completeness of the soy intake data, since soy was not the focus of these studies and most of this research was conducted prior to the recent interest in the anti-cancer effects of soy. The effect of soy/isoflavone intake has also been studied in rodents, but again these data are conflicting and provide only modest support for a protective effect. Although the relationship between soy intake and colonic cancer risk is certainly worthy of further investigation, there is, at the moment, very limited support for soy exerting a protective effect against this type of cancer.
117 citations
TL;DR: Intervention studies demonstrate that correction of relative hypogonadism in men with visceral obesity and other manifestations of the metabolic syndrome seem to decrease the abdominal fat mass and reverse the glucose intolerance, as well as lipoprotein abnormalities in the serum.
Abstract: Central or visceral obesity is recognized as a main risk factor for cardiovascular disease and type 2 diabetes mellitus. The co-existence of visceral obesity, increased blood lipid levels, hypertension and impaired glucose tolerance defines the metabolic syndrome that today is widely recognized as one of the prime factors behind cardiovascular morbidity and mortality. Endocrine disorders such as insulinoma, hypothyroidism and hypercortisolism are known to cause obesity. However, it is only hypercortisolism that is associated with increased abdominal fat accumulation. Recently, new findings have shed light on subtle endocrinopathies that are prevalent in individuals presenting with the metabolic syndrome. Such derangements are of borderline character and often fall within the normal reference range. Intervention studies demonstrate that correction of relative hypogonadism in men with visceral obesity and other manifestations of the metabolic syndrome seem to decrease the abdominal fat mass and reverse the glucose intolerance, as well as lipoprotein abnormalities in the serum. Further analysis of the underlying mechanism has also disclosed a regulatory role for testosterone in counteracting visceral fat accumulation. Longitudinal epidemiological data demonstrates that relatively low testosterone levels are a risk factor for development of visceral obesity. The primary event that triggers the initial development of visceral obesity is not known, but it seems plausible that increased activity in the hypothalamus-pituitary-adrenal axis can be of major importance.
107 citations
TL;DR: This chapter reviews the reproductive actions of phytoestrogens, comparing mechanisms of action, dose-response relationships, and human exposures, and it is likely that some humans may experience greater exposure to phy toestrogens in infancy than in any other lifestage.
Abstract: This chapter reviews the reproductive actions of phytoestrogens, comparing mechanisms of action, dose-response relationships, and human exposures. Although a wide range of biochemical actions have been reported for phytoestrogens, in vitro tests suggest that phytoestrogens may be more likely to act through receptor-mediated mechanisms than through enzyme inhibition. Epithelial cell proliferation in the reproductive tract and anestrus are well-documented actions of isoflavonoids in experimental studies of animals. However, thus far, soy-based diets have generally failed to produce epithelial proliferation in ovariectomized rats and monkeys or menopausal women, and clinical studies have produced mixed evidence for effects of soy isoflavones on the human menstrual cycle or post-menopausal gonadotropin secretion. There has been considerable interest in the use of phytoestrogens as oestrogen replacement therapy in menopausal women. Reported results of initial clinical trials have been mixed, and it is unclear whether isoflavones in presently advised doses can substantially reduce menopausal symptoms. Some recent trials with oral isoflavone supplements report reductions in hot flushes, vaginal dryness, and breast pain. There is also limited clinical evidence for protective actions of isoflavones in mammary cancer. Like other oestrogenic substances, the isoflavonoids are effective differentiating agents in rodent models of development. The consequences of these actions for humans is of interest due to the high concentrations of isoflavonoids in some infant formulae. Thus, it is likely that some humans may experience greater exposure to phytoestrogens in infancy than in any other lifestage. At the time of writing, no ill effects of such exposure have been reported.
100 citations
TL;DR: The recent discovery of a second class of oestrogen receptors, with a differential distribution among the tissues, may enable an explanation of the phytoestrogen paradox and open a way of utilizing phy toestrogen-sensitive chronic diseases such as atherosclerosis and osteoporosis.
Abstract: Phytoestrogens are paradoxical Because of their structural similarity to the physiological oestrogens, they have been assumed to increase the risk of breast cancer However, nations where the largest amounts of phytoestrogens are consumed in the diet have the lowest incidence of and rate of death from breast cancer Although these epidemiological observations do not prove that phytoestrogens have anti-cancer properties, many preclinical experiments support this concept Some indicate that early life exposure to phytoestrogens may be critical for breast cancer prevention Clinical studies to define the effect of phytoestrogens on breast cancer recurrence are underway The recent discovery of a second class of oestrogen receptors, with a differential distribution among the tissues, may enable an explanation of the phytoestrogen paradox These receptors have opened a way of utilizing phytoestrogens in the treatment of oestrogen-sensitive chronic diseases such as atherosclerosis and osteoporosis
80 citations
TL;DR: In males, an impaired function of the AMH-dependent pathway results in the persistent müllerian duct syndrome, a disorder characterized by the presence of uterus and fallopian tubes in otherwise normally virilized boys.
Abstract: In the human male fetus, testes develop by the 7th week and begin to secrete two hormones: anti-mullerian hormone (AMH) induces the regression of mullerian ducts, the anlagen of the uterus, fallopian tubes and upper vagina, upon binding to a specific membrane receptor, whereas testosterone induces the differentiation of the wolffian ducts into the epididymes, vasa deferentia and seminal vesicles. In some target tissues, testosterone is converted to dihydrotestosterone, which is responsible for masculinization of the urogenital sinus and external genitalia. Both androgens act upon binding to the same nuclear receptor. In the absence of AMH and androgen action, for example in the female or in abnormal male differentiation, the internal and external genital primordia differentiate following the female pathway, even in the absence of ovaries. In males, an impaired function of the AMH-dependent pathway results in the persistent mullerian duct syndrome, a disorder characterized by the presence of uterus and fallopian tubes in otherwise normally virilized boys. Several mutations found in the AMH and AMH-receptor genes explain the pathophysiology of this syndrome.
TL;DR: Androgens play a permissive role in the development of prostate cancer and benign prostate hyperplasia; however, there are no data to indicate that testosterone administration can lead to the progression of pre-clinical or clinical prostate cancer.
Abstract: Natural testosterone and its esters, even when applied in supraphysiological doses, rarely produce side-effects. Via a negative feedback mechanism, exogenous testosterone suppresses the production of lutenizing hormone and follicle stimulating hormone, and leads to reduced testicular sperm production and, consequently, reduced testicular volume. The main concerns for the potential adverse effects of testosterone treatment are the prostate and the cardiovascular system. Androgens play a permissive role in the development of prostate cancer and benign prostate hyperplasia; however, there are no data to indicate that testosterone administration can lead to the progression of pre-clinical or clinical prostate cancer. Whether the effects of testosterone treatment on lipid metabolism are clinically relevant is as yet undetermined. The effects of testosterone on behaviour, especially on aggression, have not been firmly established. Some androgen effects, such as virilization and coarsening of the voice, considered normal in adult men are inappropriate in women and children.
TL;DR: The soy phytoestrogens favourably influence coronary artery reactivity and inhibit the progression of atherosclerosis in the coronary, iliac and common and internal carotid arteries.
Abstract: While there have been ample studies of a cross-cultural nature and experimental evaluations establishing the cardioprotective effect of soy protein, efforts to clarify the proportion of those benefits related to its phytoestrogen content are relatively recent. In most cases, the general approach to evaluating the role of soy's phytoestrogens has been to compare the cardiovascular benefits of isolated soy protein with a comparable soy protein isolate that has been alcohol extracted. Based on that approach, soy phytoestrogens appear to lower low-density lipoprotein concentrations while increasing plasma concentrations of the high-density lipoproteins. Particularly noteworthy with respect to the high-density lipoprotein effects are the increases in apolipoprotein A-1. Phytoestrogens may also prevent the oxidation of lipoprotein particles. The soy phytoestrogens favourably influence coronary artery reactivity. They also inhibit the progression of atherosclerosis in the coronary, iliac and common and internal carotid arteries. The cardiovascular benefits of soy phytoestrogens appear to be equal for males and females.
TL;DR: The identification of its genetic basis and the study of P450c17 enzymology have recently clarified the mechanisms by which DHEA synthesis may be regulated in adrenarche, and have suggested that the lesion underlying polycystic ovary syndrome might involve a serine kinase.
Abstract: Sex steroids, both androgens and oestrogens, are made from dehydroepiandrosterone (DHEA). The biosynthesis of DHEA from cholesterol entails four steps. First, cholesterol enters the mitochondria with the assistance of a recently described factor called the steroidogenic acute regulatory protein (StAR). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia. Next, cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc. Mutations in the gene for P450scc and for its electron transfer partners, ferredoxin reductase and ferredoxin, have not been described and are probably incompatible with term gestation. Third, pregnenolone undergoes 17α-hydroxylation by microsomal P450c17. Finally, 17-OH pregnenolone is converted to DHEA by the 17,20 lyase activity of P450c17. Isolated 17,20 lyase deficiency is rare, but the identification of its genetic basis and the study of P450cl7 enzymology have recently clarified the mechanisms by which DHEA synthesis may be regulated in adrenarche, and have suggested that the lesion underlying polycystic ovary syndrome might involve a serine kinase.
TL;DR: Certain plant compounds such as isoflavonoids, flavonoids and lignans have been proposed as cancer protective compounds in populations with low incidences of prostate diseases, and soya contains the is oflavone genistein, a compound with many properties which could influence both endocrine and growth factor signalling pathways.
Abstract: Both benign hyperplasia (BPH) and cancer of the prostate are manifest in men beyond the age of 50. Approximately 50% of men greater than 50 years of age will suffer from the symptoms associated with BPH, especially from bladder outlet obstruction. With the ever-increasing proportion of the population over 65 years of age worldwide, BPH is becoming an important medical problem as the world moves into the next millennium. Cancer of the prostate is the second most commonly diagnosed cancer after skin cancer in the male population of the United States, and the second most common cause of death from cancer after that of the lung. Overall, around the world the incidence of carcinoma of the prostate is increasing annually by 2–3%. Both race and geographical location have a profound influence of the prevalence of prostate cancer worldwide. Black men in the USA have the highest incidence, while the incidence is much lower in Asian men from China, Japan and Thailand. Although the prostate gland is androgen-dependent, it is now recognized that the biological actions of endocrine-related factors, such as androgens, oestrogens, glucocorticoids and certain dietary and environmental factors, are mediated within the gland by various growth regulatory factors. The growth regulatory factors such as epidermal growth factor (EGF), keratinocyte growth factors (KGF), fibroblast growth factors (FGFs) and insulin-like growth factors II and I are mitogenic and directly stimulate cell proliferation under the modulating influence of steroid hormones. Steroids are therefore essential but not directly responsible for cell proliferation. Certain plant compounds such as isoflavonoids, flavonoids and lignans have been proposed as cancer protective compounds in populations with low incidences of prostate diseases. In particular, soya contains the isoflavone genistein, a compound with many properties which could influence both endocrine and growth factor signalling pathways.
TL;DR: Body composition affects GH secretion by way of the degree of adiposity, and free fatty acids and leptin would appear to be the messages through which adipocytes participate in the regulation of GH secretion.
Abstract: Administration of growth hormone (GH) induces changes in body composition, namely, increases in both bone and lean mass and a decrease in fatty tissue. However, the contrary issue, i.e. the way in which body composition affects the secretion of GH, is highly controversial. Disease states such as obesity and chronic hypercortisolism are associated with increased adiposity and/or the central distribution of fat. Ageing, characterized by excess adiposity, is also associated with impaired secretion of GH. In these states, both spontaneous and stimulated secretion of GH is severely impeded. At the other extreme, malnutrition and fasting are both associated with increased secretion of GH when confronted with most, if not all, stimuli. As the common factor in all of these situations is the increased or decreased adiposity, or the changes in energy homeostasis, it has been postulated that adipose tissue exerts a relevant role in the control of GH secretion in man. The link between adipose tissue and GH seems to be exerted through at least two signals produced by adipocytes: free fatty acids (FFA) and the recently cloned protein, leptin. An increase in FFA blocks secretion of GH, while a decrease in FFA enhances secretion. Leptin, a hormone whose main role is to regulate the intake of food and energy expenditure, seems to regulate GH secretion by acting at the hypothalamic level. In summary, body composition affects GH secretion by way of the degree of adiposity, and free fatty acids and leptin would appear to be the messages through which adipocytes participate in the regulation of GH secretion. This framework clarifies the metabolic control of GH, a hormone with profound metabolic activities.
TL;DR: Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase-3 (17 beta-HSD-3) deficiency and 5 alpha-reductase-2 (5 alpha-RD-2) deficiency provides natural human genetic models to elucidate androgen actions.
Abstract: Male pseudohermaphroditism due to 17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3) deficiency and 5α-reductase-2 (5α-RD-2) deficiency provides natural human genetic models to elucidate androgen actions. To date, five 17β-HSD isozymes have been cloned that catalyse the oxidoreduction of androstenedione and testosterone and dihydrotestosterone (DHT), oestrone and oestradiol. Mutations in the isozyme 17β-HSD-3 gene are responsible for male pseudohermaphroditism due to 17β-HSD deficiency. The type 3 isozyme preferentially catalyses the reduction of androstenedione to testosterone and is primarily expressed in the testes. Fourteen mutations in the 17β-HSD-3 gene have been identified from different ethnic groups. Affected males with the 17β-HSD-3 gene defect have normal wolffian structures but ambiguous external genitalia at birth. Many are raised as girls but virilize at the time of puberty and adopt a male gender role. Some develop gynaecomastia at puberty, which appears to be related to the testosterone/oestradiol ratio. Two 5α-reductase (5α-RD) isozymes, types 1 and 2, have been identified, which convert testosterone to the more potent androgen DHT. Mutations in the 5α-RD-2 gene cause male pseudohermaphroditism, and 31 mutations in the 5α-RD-2 gene have been reported from various ethnic groups. Such individuals also have normal wolffian structure but ambiguous external genitalia at birth and are raised as girls. Virilization occurs at puberty, often with a gender role change. The prostate remains infantile and facial hair is decreased. Balding has not been reported. The coexistence of both 17β-HSD-3 and 5α-RD-2 gene defects has been identified in a Turkish community. The studies of inherited enzymatic defects involving androgen biosynthesis and action highlight the importance of testosterone and DHT in male sexual differentiation and male physiology.
TL;DR: The potential beneficial effect of less prostate growth after DHT requires substantiation and, if true, must be balanced against any negative effects that might occur on bone, lipids and sexuality when a pure androgen replaces treatment with an aromatizable androgen.
Abstract: Testosterone therapy is commonly used to treat male hypogonadism, androgen deficiency of severe illness, androgen deficiency of ageing and microphallus in infancy. The effects of testosterone are mediated directly as testosterone or after conversion to either dihydrotestosterone (DHT) or oestradiol. DHT is a potent androgen and cannot be aromatized to oestrogens, therefore acting as a pure androgen. DHT has been proposed as an androgen replacement therapy, with possible advantages over testosterone in certain circumstances in the ageing population as well as in patients with gynaecomastia and microphallus. A potential advantage of DHT over testosterone as an androgen replacement therapy is the reported and seemingly paradoxically muted effects of DHT on prostate growth. The decreased effect of DHT compared with testosterone on the prostate gland of humans may be due to the decrease in intraprostatic oestradiol levels. The potential beneficial effect of less prostate growth after DHT requires substantiation and, if true, must be balanced against any negative effects that might occur on bone, lipids and sexuality when a pure androgen replaces treatment with an aromatizable androgen.
TL;DR: The increased cardiovascular morbidity and mortality demonstrated in these GH-deficient (GHD) adults reinforce the close association between the two syndromes.
Abstract: It is now recognized that growth hormone (GH) deficiency in adults represents a distinct clinical syndrome that encompasses reduced psychological well-being as well as specific metabolic abnormalities. The latter features, which include hypertension, central obesity, insulin resistance, dyslipidaemia and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. The increased cardiovascular morbidity and mortality demonstrated in these GH-deficient (GHD) adults reinforce the close association between the two syndromes. Replacement of GH in GHD adults has resulted in a marked reduction of central obesity and significant reduction in total cholesterol but little change in other risk factors, in particular insulin resistance and dyslipidaemia. The persistent insulin resistance and dyslipidaemia, together with the elevation of plasma insulin levels and lipoprotein (a) with GH replacement in these subjects are of concern. Long-term follow-up data are required to assess the impact of GH replacement on the cardiovascular morbidity and mortality of GHD adults. Further exploration of the appropriateness of the GH dosage regimens currently being employed is also indicated.
TL;DR: The potential for GH therapy to correct some of the detrimental effects of the ageing process is examined, including those associated with the hyposomatotropism of the elderly, but are less severe than those seen in younger adults with organic GH deficiency.
Abstract: Organic growth hormone (GH) deficiency in adults results in many adverse changes similar to the changes which occur in humans with increasing age. The secretion of GH from the anterior pituitary declines with increasing age. This observation, together with the changes in body composition associated with organic GH deficiency in adults, has led to the suggestion that the elderly without hypothalamic-pituitary disease are GH deficient and may benefit from GH therapy. The impact of organic disease of the hypothalamic-pituitary axis in the elderly may result in a reduction in GH secretion of up to 90%. This reduction in GH secretion is sufficient to cause a fall in the serum insulin-like growth factor-1 (IGF-1) concentration, abnormal body composition and abnormal bone turnover, although bone mineral density is unaffected. These changes are distinct from those associated with the hyposomatotropism of the elderly, but are less severe than those seen in younger adults with organic GH deficiency. In this chapter we discuss the effects of organic GH deficiency in elderly subjects and the potential effects of GH replacement therapy. We also examine the potential for GH therapy to correct some of the detrimental effects of the ageing process.
TL;DR: Although the beneficial effects of androgenic steroids in HIV-infected men have not been demonstrated clearly, short-term studies suggest that testosterone supplementation may improve metabolic outcomes in HIV's infected men with androgen deficiency.
Abstract: Hypogonadism in HIV-infected men has been well described, having a prevalence of about 30%. Its aetiology is a combination of non-specific changes from chronic and acute illness, and specific effects due to HIV infection. A depressed serum testosterone level has been associated with viral or infectious invasion of the endocrine organs, and with medications commonly used in treating HIV infection. Recently, many have noted the association between decreased serum testosterone in men and women, and the wasting syndrome of HIV infection, particularly with a reduction in lean body mass. Our understanding of the risks and benefits of testosterone therapy in non-HIV infected men has grown significantly. Treatment in this population can improve sexual function, quality of life parameters and body composition. Based on this information, a few studies have been carried out, and more are being planned to test the hypothesis that therapy with testosterone or its analogues can benefit HIV-infected men and women with wasting and/or low circulating androgen concentrations. To date, the studies have been inconclusive. Not all studies have shown a statistical benefit of androgen therapy on weight, muscle mass or quality of life. Testosterone is now available in several forms for dosing, which has improved compliance and ease of administration. Its potential risk to the prostate or serum lipids should be monitored closely. Although the beneficial effects of androgenic steroids in HIV-infected men have not been demonstrated clearly, short-term studies suggest that testosterone supplementation may improve metabolic outcomes in HIV-infected men with androgen deficiency.
TL;DR: Although the data are limited, studies of testosterone replacement in healthy older men with relative testosterone deficiency have demonstrated some modest improvements in muscle mass and strength, although the clinical and functional relevance of the muscle changes have yet to be determined.
Abstract: Normal ageing is associated with a decline in lean body mass, muscle mass and strength. The functional consequences of these changes may be significant and include falls, fractures, loss of mobility and increasing dependency. The anabolic actions of testosterone on muscle have been known for over 60 years, and replacement studies in young hypogonadal men have shown that testosterone can improve muscle mass and strength. In addition, the supraphysiological replacement of testosterone in young eugonadal men has also been shown to increase muscle mass and improve strength. Although the data are limited, studies of testosterone replacement in healthy older men with relative testosterone deficiency have demonstrated some modest improvements in muscle mass and strength, although the clinical and functional relevance of the muscle changes have yet to be determined. More data and experience are needed before testosterone can be advocated for the prevention or reversal of sarcopenia in the ageing male.
TL;DR: Owing to its tolerability and its suitability for use in the elderly, the GHRH+arginine test is the best alternative choice and is at least as sensitive as the ITT provided that appropriate cut-off limits are given.
Abstract: The aim of this review is to answer two questions. The first question is: is there any alternative provocative test equal to, or even better than, the insulin-tolerance test (ITT), the so-called gold standard, for the diagnosis of growth hormone deficiency (GHD) in adults and the elderly? The answer is 'yes'. In fact, when combined with arginine or pyridostigmine, growth hormone-releasing hormone (GHRH) becomes one of the most potent and reproducible tests for distinguishing patients with severe GHD from normal subjects. Owing to its tolerability and its suitability for use in the elderly, the GHRH + arginine test is the best alternative choice and is at least as sensitive as the ITT provided that appropriate cut-off limits are given. The second question is: is there any therapeutic approach alternative to recombinant human growth hormone (rhGH) for adult and elderly patients with GHD and/or for the somatopause? At present, the answer is 'no'. Growth hormone (GH)-releasing substances need the functional integrity of somatotroph cells to induce the release of growth hormone. Probably only patients with childhood-onset, isolated GHD (frequently hypothalamic-dependent) could benefit from treatment with GHRH or growth hormone secretagogues (GHS). Whenever restoration of the activity of the GH/insulin-like growth factor-1 (IGF-1) axis in the elderly would be of use, GHRH and/or GH secretagogues would be good candidates. In fact, the existence of a considerable pool of releasable growth hormone has been demonstrated in the elderly.
TL;DR: The cDNA corresponding to the luteinizeng hormone (LH) receptor (LHR) has been cloned, leading to the identification of a novel family of G-protein-coupled receptors, which opened the field of genetic study of the receptors.
Abstract: Over the past few years, knowledge of the structure of gonadotropin receptors and their mode of action has rapidly advanced. The cDNA corresponding to the luteinizeng hormone (LH) receptor (LHR) has been cloned, leading to the identification of a novel family of G-protein-coupled receptors. The follicle stimulating hormone (FSH) receptor (FSHR) was thereafter cloned by cross-hybridization with the LHR. Structure—function relationships have been studied by mutagenesis experiments in several laboratories. The cloning and chromosomal localization to chromosome 2p21 of the two human gonadotropin receptor genes has provided insights into their evolutionary relationships. The LHR and FSHR genes are very large and contain 10 and 11 exons respectively. The obtention of monoclonal antibodies against the receptors resulted in the characterization of the receptor proteins. These antibodies also allowed the study of receptor expression in target cells in physiological and pathological conditions. The internalization of the LHR has been studied by electron microscopy. A mechanism of receptor-mediated transcytosis through the endothelial cells of the testes has been described for the LHR. The polarized expression of receptors has been studied. The cloning of gonadotropin receptor genes has opened the field of genetic study of the receptors. Inactivating mutations of the LHR have been described in Leydig cell agenesis or hypoplasia. Different phenotypes, including complete pseudohermaphroditism, ambiguous genitalia and male phenotype, have been described. In the case of the FSHR, only one mutation has been reported in familial ovarian dysgenesis with primary amenorrhea. Related males have variable alterations of spermatogenesis and fertility. Constitutive mutations of the LHR have been reported in familial testotoxicosis. One similar mutation has also been described for the FSHR. Such mutations may lead to the development of a model of receptor activation.
TL;DR: A judgement on whether DHEA replacement has a place in preventing age-related disabilities could be determined only on the basis of results from studies of long-term D HEA replacement in elderly people.
Abstract: There are many hormonal changes that occur with ageing in humans, of which the most dramatic and intriguing change occurs for the adrenal androgenic steroid dehydroepiandosterone (DHEA). There are tantalizing epidemiological data demonstrating a significant association between the changes in circulating DHEA level and changes in the incidence of malignancy, atherosclerosis, Alzheimer's disease and other age-related changes. The pharmacological effects in animals such as rodents and rabbits have demonstrated many beneficial effects, for example increased immune function, the prevention of atherosclerosis, cancer, diabetes and obesity, and the improvement of memory. Clinical studies carried out in small groups of subjects have clearly demonstrated that the administration of DHEA to the elderly increases many hormone levels, including that of insulin-like growth factor-1, (free and total) testosterone, dihydrotestosterone, oestrone and oestradiol. It remains to be clearly defined whether these changes are clinically beneficial, and there is only insufficient information on the side-effects on long-term use. Results from short-term intervention studies in small groups of subjects have not demonstrated any convincing beneficial effects so far. A judgement on whether DHEA replacement has a place in preventing age-related disabilities could be determined only on the basis of results from studies of long-term DHEA replacement in elderly people.
TL;DR: Alarming abnormalities in the level of circulating anabolic hormones have recently been described, suggesting that anabolic hormone supplementation may be rational therapy for patients with COPD.
Abstract: Chronic obstructive pulmonary disease (COPD) afflicts millions of people and is severely disabling. Exercise intolerance is usually the chief complaint. There are few effective therapies. Pulmonary rehabilitation seeks to return the patient to the highest possible level of function but cannot reverse the underlying pulmonary abnormalities. Several lines of evidence have recently pointed to abnormalities of the muscles of ambulation as a remediable source of exercise intolerance in COPD. Possible mechanisms of the muscle abnormalities include deconditioning, malnutrition, low levels of anabolic hormones and, perhaps, a specific myopathy. To date, most reports of attempts to reverse muscle dysfunction in COPD have focused on exercise training. However, abnormalities in the level of circulating anabolic hormones have recently been described, suggesting that anabolic hormone supplementation may be rational therapy for these patients. Accumulating evidence that anabolic steroids increase muscle mass and improve strength in older men is encouraging trials of anabolic steroids in men with COPD.
TL;DR: This chapter reviews the basis and scope for various clinical applications of gonadotropin and androgen therapy as an adjunct to the standard medical care of chronic renal failure and the therapeutic possibilities implied by experimental and clinical findings suggesting that uraemic hypogonadism may be a functional state of gonadic deficiency.
Abstract: Chronic renal failure, dialysis and transplantation have major effects on male reproductive health because of the impairment of spermatogenesis, steroidogenesis and sexual function. Hypothalamo-pituitary testicular dysfunction in uraemia is manifest clinically as delayed growth and puberty, sexual dysfunction, androgen deficiency, impaired spermatogenesis and infertility. Apart from renal anaemia, there are at present no proven indications for androgen therapy in chronic renal failure. This chapter reviews the basis and scope for various clinical applications of gonadotropin and androgen therapy as an adjunct to the standard medical care of chronic renal failure. The therapeutic possibilities implied by experimental and clinical findings suggesting that uraemic hypogonadism may be a functional state of gonadotropin deficiency are emphasized.
TL;DR: Although emerging data demonstrate modest gains in fat-free mass in HIV-infected men given replacement doses of testosterone, it is unclear whether testosterone supplementation can produce clinically meaningful changes in muscle function and disease outcome in patients with wasting disorders.
Abstract: Testosterone-induced nitrogen retention in castrated male animals, eunuchoidal men, prepubertal boys and women, and the sex-related differences in the size of the muscles between male and female animals, have been cited as evidence that testosterone has anabolic effects. Recent studies have reported that replacement doses of testosterone in hypogonadal men and supraphysiological doses in eugonadal men increase fat-free mass, muscle size and strength. These effects have provided the rationale for exploring these anabolic applications in sarcopenic states. Although emerging data demonstrate modest gains in fat-free mass in HIV-infected men given replacement doses of testosterone, we do not know whether testosterone supplementation can produce clinically meaningful changes in muscle function and disease outcome in patients with wasting disorders.
TL;DR: In this chapter, the changes in androgens as women age are reviewed, and the rationale for physiological androgen, specifically testosterone replacement, in women is addressed.
Abstract: Androgens have an important physiological role in women. Not only are they the precursor hormones for oestrogen production in the ovaries and extragonadal tissues, but they also appear to act directly, via androgen receptors, throughout the body. Androgen levels decline with increasing age in women, who may experience a variety of physical symptoms secondary to androgen depletion, as well as physiological changes that affect their quality of life. In this chapter, the changes in androgens as women age are reviewed, and the rationale for physiological androgen, specifically testosterone replacement, in women is addressed.
TL;DR: Structural alterations leading to malfunction of the AR are associated with variable inhibition of virilization despite normal or even supranormal serum levels of androgens, which has led to the characterization of the distinct molecular steps involved in the normal androgen action pathways that are inhibited in the androgen insensitivity syndrome.
Abstract: Knowledge of the physiology of male sexual differentiation and the clinical presentation of androgen insensitivity syndromes (AIS) has led to an increasing understanding of the mechanisms of androgen action. Androgens induce their specific response via the androgen receptor (AR), which in turn regulates the transcription of androgen-responsive target genes. The androgen-dependent development of male genital structures and the induction of the normal male phenotype depends on the presence of an intact AR. Structural alterations leading to malfunction of the AR are associated with variable inhibition of virilization despite normal or even supranormal serum levels of androgens. The mapping, cloning and sequencing of the AR gene have facilitated new insights into the study of androgen action. Functional investigation of the normal and the mutant AR in vivo as well as in vitro has led to the characterization of the distinct molecular steps involved in the normal androgen action pathways that are inhibited in the androgen insensitivity syndrome.