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Risks versus benefits of testosterone therapy in elderly men.

'Andropause', like menopause, has received significant attention in recent years. It results in a variety of symptoms experienced by the elderly. Many of these symptoms are nonspecific and vague. For this reason, many authors have questioned the value of androgen replacement in this population. Also in dispute is the normal cutoff level for testosterone beyond which therapy should be initiated, and whether to measure free or total testosterone. Testosterone levels decline with age, with the lowest level seen in men older than 70 years. This age-related decline in testosterone levels is both central (pituitary) and peripheral (testes) in origin. With aging, there is also a loss of circadian rhythm of testosterone secretion and a rise in sex hormone binding globulin (SHBG) levels. Total testosterone level is the best screening test for patients with suspected hypogonadism. If the total testosterone concentration is low, free testosterone levels should be obtained. Prostate cancer remains an absolute contraindication to androgen therapy. Testosterone replacement results in an improvement in muscle strength and bone mineral density. Similar effects are observed on the haematopoietic system. Data on cognition and lipoprotein profiles are conflicting. Androgen therapy can result in polycythemia and sleep apnoea. These adverse effects can be deleterious in men with compromised cardiac reserve. We recommend that elderly men with symptoms of hypogonadism and a total testosterone level <300 ng/dl should be started on testosterone replacement. This review discusses the pros and cons of testosterone replacement in hypogonadal elderly men and attempts to answer some of the unanswered questions. Furthermore, emphasis is made on the regular follow-up of these patients to prevent the development of therapy-related complications.

Aged↗

Influence of sex on drug kinetics in man.

Very few investigations in man have been specifically devoted to the influence of sex on drug kinetics. Although the potential role of various factors such as the phase of the menstrual cycle, hormonal steroid contraceptive use, menopause or andropause is virtually never taken into account, sex-linked differences in drug kinetics do exist for a limited number of substances such as certain antibiotics, a few tricyclic antidepressants, lithium and aspirin. These sex-linked differences are relatively minor from a quantitative standpoint and appear to be due chiefly to differences in body composition and activity of circulating enzymes and hormones. On the basis of present knowledge, in general these differences in drug kinetics do not warrant modifying dosage as a function of sex.

Analgesics↗

The cell cycle and hormonal fluxes in Alzheimer disease: a novel therapeutic target.

Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease (AD) including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. Strong evidence suggests that each one contributes to disease pathogenesis, though none of these mechanisms result in all the downstream changes that occur during the course of AD. For this reason, we and others have begun the search for a causative factor that predates known features found in AD, and that might be a fundamental initiator of the pathophysiological cascade. In this regard, we propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during AD is a potential causative factor that would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of AD include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Given the early and presumably devastating consequences of cell cycle re-entry, we have made a concerted effort to elucidate the initiating factor that drives aberrant mitotic re-entry in AD. As a result of the gender bias present in AD, we suspect that postmenopausal and andropausal hormones may be involved and, with this in mind, in this review we specifically focus on the gonadotropins. Therapeutic interventions targeted at gonadotropins, if they are indeed the driving mitogenic force, could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.

Alzheimer Disease↗

Frailty of older age: the role of the endocrine--immune interaction.

The so-called demographic transition has changed the age structure of the population worldwide, with profound effects on societal organization. The growing number and percentage of old and very old people has compelled the scientific community to focus on age related diseases and peculiar consequences of aging itself such as disability and frailty. Understanding the pathophysiology of frailty, a syndrome characterized by a reduced functional reserve and impaired adaptive capacity that results from cumulative declines of multiple subsystems, and causes increased vulnerability to adverse outcomes, is a major topic in aging research. Aging processes induce multiple changes in the hormones network (menopause, andropause, somatopause and adrenopause), in the immune system, and can modulate their efficiency and effectiveness in determining a response to stressors. These triggering events can unmask frailty in older people. Starting from these assumptions, we analyzed the relationship of the endocrine and immune networks in aging and in the different domains that are characteristically associated with the frailty syndrome, such as disability and sarcopenia, as well as in diseases related to aging such as Alzheimer's dementia and Congestive Heart Failure.

Aged↗

Selective androgen receptor modulators in drug discovery: medicinal chemistry and therapeutic potential.

Modulation of the androgen receptor has the potential to be an effective treatment for hypogonadism, andropause, and associated conditions such as sarcopenia, osteoporosis, benign prostatic hyperplasia, and sexual dysfunction. Side effects associated with classical anabolic steroid treatments have driven the quest for drugs that demonstrate improved therapeutic profiles. Novel, non-steroidal compounds that show tissue selective activity and improved pharmacokinetic properties have been developed. This review provides an overview of current advances in the development of selective androgen receptor modulators (SARMs).

Androgen Antagonists↗

Testosterone deficiency and mood in aging men: pathogenic and therapeutic interactions.

In contrast to women, men do not experience a sudden cessation of gonadal function comparable to menopause. However, there is a progressive reduction in hypothalamic-pituitary-gonadal (HPG) function in aging men: testosterone (T) levels decline through both central (pituitary) and peripheral (testicular) mechanisms and there is a loss of the circadian rhythm of T secretion. In cohorts of men 75 years of age, mean plasma T levels are 35% lower than comparable young men, and more than 25% of men over 75 appear to be T-deficient. Such age-associated T deficiency, which has been termed 'andropause', is thought to be responsible for a variety of symptoms experienced by elderly men, such as weakness, fatigue, reduced muscle and bone mass, impaired haematopoiesis, oligospermia, sexual dysfunction, depression, anxiety, irritability, insomnia and memory impairment. However, it has been difficult to establish correlations between these symptoms and plasma T levels. Nevertheless, there is some evidence that T replacement leads to symptom relief, particularly with respect to muscle strength, bone mineral density, and haematopoiesis. Studies to date on the specific association between psychiatric symptoms, such as depressed mood, and T levels have been methodologically flawed. Overall, data suggest that although hypogonadism is not central to major depressive disorder (MDD), HPG hypofunction may have aetiological importance in mild depressive conditions, such as dysthymia.

Age Factors↗

Brown-Séquard revisited: a lesson from history on the placebo effect of androgen treatment.

BACKGROUND: In 1889, Brown-Séquard, aged 72, reported dramatic rejuvenating effects after self-administering testicular extracts of dogs and guinea-pigs. His report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. More recently, the male ageing process has been attributed to partial androgen deficiency, or "andropause", and testosterone treatment is claimed to improve well-being in middle-aged and elderly men. DESIGN: We prepared extracts from five dog testes using Brown-Séquard's methods and assayed testosterone concentrations. RESULTS: Testosterone concentrations were four orders of magnitude less than that required for a biological effect. CONCLUSIONS: Our study illustrates the marked placebo response that can be evoked by androgen treatment. It cautions against the empirical use of testosterone treatment for older men, unless a diagnosis of hypogonadism has been substantiated.

Aged↗

Testosterone: use, misuse and abuse.

Testosterone is among the oldest drugs in medicine. It has a long efficacy and safety record for its prime role of androgen replacement therapy in men with androgen deficiency. Testosterone and synthetic analogue androgens have also been used in pharmacological androgen therapy (PAT) to produce androgenic effects on marrow, muscle or bone. Although PAT is increasingly being superseded by newer, more expensive drugs, androgens remain cost-effective in many older applications. Androgen misuse is the systematic over-prescribing for unproven medical indications. Misuse is increasingly evident for male ageing ("andropause") and some other clinical conditions. Further trials for new indications for androgens require reliable safety data, but rising costs may make it increasingly attractive to circumvent the need for evidence by promoting off-label mass marketing. Androgen abuse is the illicit self-administration of often massive doses of androgens for non-medical purposes - notably power sports and body building. In parallel with effective detection reducing androgen abuse in elite sports, more focus is needed on non-sporting cosmetic, recreational and occupational androgen abuse. Despite ongoing androgen misuse and abuse, testosterone remains under-prescribed for younger men with classical androgen deficiency that frequently remains undiagnosed.

Aging↗

[On the healthy male aging: hormonal aspects].

Authors present select problems performed in the "Geneva Manifesto" published by the International Society for the Study of the Aging Male in February 1998 and pay the special attention on the inaccuracy connected with a commonly used name andropause. Additionally they present actual metabolic and clinical aspects resulting from the hormonal disturbances in aging men (hypotestosteronemia, decline in DHEA and hGH).

Aged↗

[Endocrinology 1997-1998].

The author presents an account on advances in endocrinology in 1997-1998, starting by mentioning the Nobel prize for physiology and medicine in 1998 and the discovery of nitric oxide as an active substance. Subsequently the author discusses data on "new gerontology", i.e. hormonal aspects of the menopause, andropause, adrenopause and somatopause. Endocrinological contributions to oncology pertain in particular to the discovery of active substances which inhibit neovascularization (endostatins) and some new aspects of the action of antioestrogens and oestrogens. The possible action of hormonal factors in neurodegenerative processes are obvious in ubiquitine, CREB and "heat shock proteins". New types of Ca-channels were detected, in particular "promiscuous" channels, conveying Ca as well as Na, which can be influenced by endogenous ouabain. Subsequently attention is paid to ryanodine receptors and compounds acting as Ca on the sensor for Ca in the parathyroid bodies and inhibition parathormone secretion. The greatest future advances will be achieved obviously in the sphere of oncology, gerontology and hormonal analogues with unforeseen effects.

Calcium Channels↗

[Rejuvenating hormones].

The clinical and biological syndromes of menopause, andropause, somatopause and adrenopause are presented successively. Various substitutive hormonotherapies (including melatonin) are considered according to their efficacy, risks and cost.

Antioxidants↗

[Are the hormones of youth carcinogenic?].

The decrease of different hormones during aging could play some role in the decline of physical and mental functions of elderly people. Whereas estrogen secretion is almost abolished in menopause, there is a gradual decline of other hormones such as testosterone (T) in men as well as growth hormone (GH) or dehydropepian-drosteronesulfate (DHEAS). As "pause" means cessation in Greek, the term of "clise" (decline) seems to be more appropriate for the 3 latter hormones (e.g. androclise versus andropause). The administration of T and GH to elderly men can increase muscle mass, bone mineral content and decrease fat mass. Long term treatment with estrogens can decrease cardiovascular mortality of postmenopausal women. DHEA administration increases perceived well-being in both sexes. However treatments with T and DHEA risk to induce the growth of an occult prostate cancer and a long term treatments with estrogen can increase the risk of breast cancer. There is a strong association between circulating IGF-I levels and the relative risks of breast and prostate cancer. We hypothesize that the decrease of the latter hormones partially protects against the increasing occurrence of hormonosensitive cancers with aging. The administration of these hormones could oppose this process and increase the carcinogenic risk.

Aging↗

Insulin-like growth factor-binding protein-3 is associated with the presence and extent of coronary arteriosclerosis

Aging is associated with the progression of arteriosclerosis and the decline of several endocrine functions. We therefore investigated the association of coronary arteriosclerosis with hormones, the serum concentrations of which change during aging. Coronary angiograms of 189 men <70 years old were evaluated by 3 semiquantitative score systems to estimate the extent of focal and diffuse vessel wall alterations. Fasting sera were analyzed for levels of glucose, lipids, thyroid-stimulating hormone, insulin, insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone-binding globulin (SHBG). After adjustment for age, body mass index, and waist-to-hip ratio, 92 patients with >/=1 stenoses >70% differed from 97 patients without such focal lesions by higher serum levels of glucose, total and LDL cholesterol, and apolipoprotein (apo) B, as well as by lower serum levels of IGFBP-3. Multivariate analyses revealed significant and independent correlations of all 3 coronary scores with LDL cholesterol (or apoB) and IGFBP-3; of 2 coronary scores with age, glucose, and insulin; and of 1 score with IGF-I. No significant correlations existed for waist-to-hip ratio (or body mass index) and DHEAS (or testosterone or SHBG). IGFBP-3 explained 9% to 14% and 3.5% to 10% of the variances of focal and diffuse lesions, respectively. In conclusion, IGFBP-3 and, with much less strength and consistency, insulin and IGF-I, but not markers of hypothyroidism, adrenopause, and andropause, have statistically significant and independent associations with coronary arteriosclerosis in men.

Journal Article↗

Insulin-like growth factor-binding protein-3 is associated with the presence and extent of coronary arteriosclerosis

Aging is associated with the progression of arteriosclerosis and the decline of several endocrine functions. We therefore investigated the association of coronary arteriosclerosis with hormones, the serum concentrations of which change during aging. Coronary angiograms of 189 men <70 years old were evaluated by 3 semiquantitative score systems to estimate the extent of focal and diffuse vessel wall alterations. Fasting sera were analyzed for levels of glucose, lipids, thyroid-stimulating hormone, insulin, insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone-binding globulin (SHBG). After adjustment for age, body mass index, and waist-to-hip ratio, 92 patients with >/=1 stenoses >70% differed from 97 patients without such focal lesions by higher serum levels of glucose, total and LDL cholesterol, and apolipoprotein (apo) B, as well as by lower serum levels of IGFBP-3. Multivariate analyses revealed significant and independent correlations of all 3 coronary scores with LDL cholesterol (or apoB) and IGFBP-3; of 2 coronary scores with age, glucose, and insulin; and of 1 score with IGF-I. No significant correlations existed for waist-to-hip ratio (or body mass index) and DHEAS (or testosterone or SHBG). IGFBP-3 explained 9% to 14% and 3.5% to 10% of the variances of focal and diffuse lesions, respectively. In conclusion, IGFBP-3 and, with much less strength and consistency, insulin and IGF-I, but not markers of hypothyroidism, adrenopause, and andropause, have statistically significant and independent associations with coronary arteriosclerosis in men.

Journal Article↗

[Andropenia and hormone-replacement therapy in men].

The andropause (andropaenia) or PADAM-syndrome represents a combination of clinical and laboratory symptoms, developed during aging. The most frequently reported clinical feature is erectile dysfunction. From the laboratory parameters the most typical finding is low normal or reduced serum testosterone levels. Very useful questionnaires have been developed helping in diagnosing the PADAM syndrome. Nowadays the hormonal replacement therapy with testosterone derivatives is considered to be the "gold standard". It has positive impact on the cardiovascular risk profile and its different components. This therapy is being prescribed on clear indications and according to strict rules. Available preparations in our country are the injectable and oral ones. Replacement therapy with other hormones is still not a part of clinical practice.

Aging↗

[Social medicine aspects of the aging man].

The potential for good health is largely dependent on the prevention and reduction of early onset of fatal disease and death. The male population, in particular, is at risk from early onset of fatal disease and death. Prevention strategies must be developed in order to reduce the risk factors leading to the currently most common causes of death (heart disease, cancer, accidents). Due to the increase in life expectancy, however, other illnesses generally affecting the elderly population (osteoporosis, dementia, cancer, heart attack, incontinence etc.) are gaining in significance. The above average reduction in life expectancy in men can be counteracted particularly through preventative measures and the active promotion of good health. In particular risk factors, such as, smoking, overweight, high blood pressure and metabolic disease, are responsible for the high mortality rate in men. New research areas must be defined for the male population, which particularLy focus on the ageing male. In the field of age related illness, gender specific investigations are definitely required. The main focus has to be on therapy and prevention of those diseases and their subsequent debilitating effects, that commonly effect the elderly. Particularly with men there is still a deficit of information with regards the role of hormones and their relationship with andropause and ageing.

Adolescent↗

[Hormone profile in the aging man].

During male ageing serum levels of testosterone, free testosterone, DHEA, growth hormone and maltonin decrease in contrary to the increase of FSH, LH, SHBG. Estradiol, Prolaktin and dihydrotestosterone show no significant changes. The terminus "andropause" is not correct, because there is no sudden decrease in sexual hormones, which is seen in the female (menopause). We should characterize the hormonE changes as "partial endocrine variations of the ageing male" or "partial androgen deficiency of the ageing male". Wether hormone replacement therapy leads to delay of ageing or increase of well being in ageing males can only be demonstrated in long term studies over ten years. Otherwise an evidence is required to demonstrate that long time hormone replacement therapy will not lead to tumour induction or increase of tumour growing.

Adolescent↗

[Pituitary diseases in elderly patients with chronic renal insufficiency].

Chronic renal failure (CRF) in the elderly is a cause of multiple endocrine dysfunctions. The three most common pituitary axes involved are the thyrotrope, lactotrope and gonadotrope axes. Thyroid dysfunction may be the consequence of thyroid or pituitary failure. Hyperprolactinemia results in gonadal failure and is present in 30% of patients. Early presentation of menopause and andropause are common in patients with CRF. Sexual hormonal replacement is controversial and must be individually tailored. We propose a systematic screening in the elderly with CRF: determination of TSH, TPO antibodies and cervical palpation, measures of PRL, LH, FSH and testosterone to explore lactotrope and gonadotrope axis.

Aged↗