Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25?mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while β-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment.

The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and β-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain.

In conclusion, the present study demonstrates that 25?mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results.     

Association of serum calcium with serum sex steroid hormones in men in NHANES III

Abstract

Background: Bone is a positive regulator of male fertility, which indicates a link between regulation of bone remodeling and reproduction or more specifically a link between calcium and androgens. This possibly suggests how calcium is linked to prostate cancer development through its link with the reproductive system. We studied serum calcium and sex steroid hormones in the Third National Health and Nutrition Examination Survey (NHANES III).

Methods: Serum calcium and sex steroid hormones were measured for 1262 men in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide (AAG), and sex hormone binding globulin (SHBG) by categories of calcium (lowest 5% [<1.16?mmol/L], mid 90%, top 5% [≥1.30?mmol/L]).

Results: Levels of total and free testosterone, total estradiol or AAG did not differ across categories of serum calcium. Adjusted SHBG concentrations were 36.4 for the bottom 5%, 34.2 for the mid 90% and 38.9?nmol/L for the top 5% of serum calcium (P_trend?=?0.006), free estradiol levels were 0.88, 0.92 and 0.80?pg/ml (P_trend?=?0.048).

Conclusions: This link between calcium and sex steroid hormones, in particular the U-shaped pattern with SHBG, may, in part, explain why observational studies have found a link between serum calcium and risk of prostate cancer.     

Are the Aging Male’s Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire suitable for the screening of late-onset hypogonadism in aging Chinese men?

Abstract

The Aging Male’s Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire have been widely used for screening men suspected of late-onset hypogonadism (LOH). We evaluated the consistency of the two questionnaires with sex hormone levels. A total of 985 men completed the two questionnaires, as well as an analysis of the serum levels of total testosterone (TT), bioavailable testosterone (BT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL) and sex hormone-binding globulin (SHBG). No correlation was observed between any hormone level and the psychological or somatic section of the AMS score, whereas the sexual section was correlated with the levels of FT, LH, FSH, SHBG and BT. Significant correlations were observed between the result of the two questionnaires and these hormone levels. When LOH was defined as TT?<?300?ng/dl and FT?<?5?ng/dl, the sensitivity and specificity of the AMS scale were 54.0% and 41.2% compared with 78.7% and 14.8% for the ADAM questionnaire. Several sex hormone levels correlated with the two questionnaires, but neither of these questionnaires had sufficient sensitivity and specificity. It is necessary to provide a new questionnaire applicable to the Chinese population to screening LOH.     

Murine models of life span extension

Mice are excellent experimental models for genetic research and are being used to investigate the genetic component of organismal aging. Several mutant mice are known to possess defects in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) neurohormonal pathway and exhibit dwarfism together with extended life span. Their phenotypes resemble those of mice subjected to caloric restriction. Targeted mutations that affect components of this pathway, including the GH receptor, p66Shc, and the IGF-1 receptor (IGF-1R), also extend life span; mutations that affect IGF-1R or downstream components of the pathway decouple longevity effects from dwarfism. These effects on life span may result from an increased capacity to resist oxidative damage.     

Circulating testosterone and estradiol,autonomic balance and baroreflex sensitivity in middle-aged and elderly men with heart failure

Abstract

Background: Heart failure (HF) is considered as a cardiogeriatric syndrome. Its fundamental pathophysiological feature is autonomic imbalance (and associated abnormalities within cardiovascular reflex control), but recent evidence suggests the involvement of deranged hormone metabolism. Both these neural and endocrine pathologies have serious clinical and prognostic consequences in patients with HF. We investigated the relations between autonomic status, baroreflex sensitivity (BRS) and hormone status in men with mild systolic HF.

Methods: We examined 46 men with stable systolic HF (age: 62?±?10 years, NYHA class I/II: 10/36 [22%/78%], ischemic aetiology: 72%, left ventricular ejection fraction: 32?±?8%). Serum hormone levels (i.e. total testosterone [TT], dehydroepiandrosterone sulphate [DHEAS], oestradiol [E2], insulin-like growth factor type 1 [IGF-1] and cortisol) were assessed using immunoassays. Estimated free testosterone (eFT) was estimated using the Vermeulen’s equation. Heart rate variability (HRV) was assessed in time and frequency domains, based on 10-min resting recordings. BRS was estimated using the sequence method (BRS-Seq) and the phenylephrine test (BRS-Phe).

Results: Deficiencies in circulating TT, eFT, DHEAS and IGF-1 (defined as a serum hormone ≤the 10th percentile calculated for the adequate age category in the cohort of healthy men) were found in respectively 13%, 30%, 55% and 93% of men with systolic HF. Serum SHBG ≥50?nmol/L and cortisol ≥700?nmol/L characterised, respectively 44% and 29% of men with HF. In multivariable models after the adjustment for clinical variables, the following relationships were found in examined men: DHEAS and SDNN (time domain of HRV defined as a standard deviation of average R–R intervals) (β?=?0.29, p?=?0.03); E2 and: HRV-LF (ms²) (β?=?0.37, p?=?0.01), HRV-HF (ms²) (β?=?0.44, p?=?0.02) and BRS-Phe (β?=?0.51, p?=?0.008); TT and: HRV-HF (%) (β?=?0.35, p?=?0.02), HRV-LF/HF ratio (β?=??0.35, p?=?0.02) and BRS-Seq (β?=?0.33, p?=?0.04).

Conclusions: The observed associations between reduced circulating androgens, oestrogens and lower HRV and depleted BRS, irrespectively of HF severity suggest the pathophysiological links between these two mechanisms. These results constitute the premises to investigate whether the pharmacological supplementation of depleted hormones would enable to restore the autonomic balance and improve the efficacy of reflex control within the cardiovascular system in men with systolic HF.     

Growth hormone,somatomedins and men's health

According to current basic science as well as the clinical literature, human growth hormone has become an important topic in the field of anti-aging medicine. It is well known that the administration of human growth hormone compensates for the dwarfism syndrome in growth hormone-deficient children and growth hormone is also established as a substitution therapy for adults with pituitary deficiency. The effects mediated by growth hormone comprise an increase in muscle mass, a decrease in body fat, improved physical condition, oxygen consumption and overall quality of life, an improvement of the ratio of high-density lipoprotein to low-density lipoprotein, as well as an increase in bone density. Due to the insulin antagonistic effect of growth hormone as well as its insulin-like growth factor-1-mediated mitogenic effect, there is reason to doubt the safety of administering growth hormone outside the framework of approved indications. In an ongoing study, we are evaluating whether growth hormone and somatomedins might be of importance in the regulation of male sexual performance, including penile erection.     

Estrogen receptor alpha single nucleotide polymorphism as predictor of diabetes type 2 risk in hypogonadal men

Abstract

Estradiol (E2) is, apart from its role as a reproductive hormone, also important for cardiac function and bone maturation in both genders. It has also been shown to play a role in insulin production, energy expenditure and in inducing lipolysis. The aim of the study was to investigate if low circulating testosterone or E2 levels in combination with variants in the estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) genes were of importance for the risk of type-2 diabetes. The single nucleotide polymorphisms rs2207396 and rs1256049, in ESR1 and ESR2, respectively, were analysed by allele specific PCR in 172 elderly men from the population-based Tromsø study. The results were adjusted for age. In individuals with low total (≤11?nmol/L) or free testosterone (≤0.18?nmol/L) being carriers of the variant A-allele in ESR1 was associated with 7.3 and 15.9 times, respectively, increased odds ratio of being diagnosed with diabetes mellitus type 2 (p?=?0.025 and p?=?0.018, respectively). Lower concentrations of E2 did not seem to increase the risk of being diagnosed with diabetes. In conclusion, in hypogonadal men, the rs2207396 variant in ESR1 predicts the risk of type 2 diabetes.     

Correlation between sex hormone levels and obesity in the elderly male

Objective: To investigate the levels of sex hormones and androgen receptor (AR) in elderly male patients and to explore a possible correlation with obesity. Methods: The cross-sectional study included 314 Elderly males (age ≥ 65 year). Of these subjects, 104 were healthy (age range 65–92 year; mean 71.38 ± 5.154 year), 74 were obese (65–87 year; 71.32 ± 4.74 year), and 111 were overweight (65–85 year; 71.43 ± 5.03 year). The following parameters were measured: total testosterone (TT), free testosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), estradiol (E2), luteinizing hormone, follicle-stimulating hormone and AR. Results: (i) The levels of TT and SHBG in the obesity group were significantly lower than those in non-obese subjects. (ii) Body mass index (BMI) negatively correlated with TT and SHBG. (iii) Multiple regression analysis revealed that TT (β: ?0.230; p = 0.045) and SHBG (β: ?0.163; p = 0.02) were statistically correlated with BMI. Conclusion: Testosterone levels in the obese population were significantly lower than in the non-obese population and there is a significant association between testosterone levels and the extent of obesity.     

Metabolic and hormonal responses to different resistance training systems in elderly men

Objective: To compare acute and sub-acute responses in hormonal profile and metabolic parameters in elderly people who participated in two methods of strength training (ST) with equalized loads.

Methods and materials: A total of 12 elder individuals (65?±?3 years) were randomly assigned to two training methods: constant intensity (CI, 3 sets of 10 repetitions with 75% of 1RM) and variable intensity (VI, 1st set: 12 repetitions at 67% of 1RM?>?2nd set: 10 repetitions at 75% of 1RM and 3rd set: 8 repetitions at 80% of 1RM). Both methods included the following exercises: leg press, knee extension, and squat with 1?min rest intervals between sets. Free speed of execution and maximum range of movement were encouraged throughout each set for both protocols. Blood samples were analyzed included glucose, testosterone (T), cortisol (C), T/C rate, growth hormone (GH), and lactate at 2 and 24?h post intervention.

Results: There were no observed differences in glucose, testosterone, GH, and lactate concentrations both at 2 and 24?h after the execution of the two training methods. However, significant increases in the levels of T/C rate and decrease on cortisol were observed immediately post exercise for both protocols.

Conclusions: Although no significant differences were observed between the two interventions in relation to the hormonal and metabolic parameters analyzed, both training methods promoted a favorable response, with a slight superiority noted for the CI method relative to the hormonal profile.     

Gonadotrophin receptor hormone analogues in combination with add-back therapy: an update

Gonadotrophin receptor hormone analogues (GnRHa) have been used in a range of sex hormone-dependent disorders. In the management of premenstrual syndrome, they can completely abolish symptoms. The success of GnRHa in the treatment of endometriosis and adjuvant therapy in the management of fibroids is proven. This efficacy does not come without a cost and the side-effects of the hypo-estrogenic state have limited their application. The use of add-back therapy to counter these effects has enabled wider application, longer durations of treatment and an increase in compliance. This review article is an update on the evidence supporting gonadotrophin receptor hormone analogues in combination with add-back therapy.     

Soy protein based supplementation supports metabolic effects of resistance training in previously untrained middle aged males

Abstract

Objective.?To determine changes in body composition, physical performance, metabolic and hormonal parameters induced by lifestyle counselling, resistance training and resistance training with soy protein based supplemention in middle aged males.

Design.?Randomised controlled study consisting of resistance training without (RT-G) or with (RTS-G) a soy protein based supplement and a control group with lifestyle education only (LE-G).

Subjects.?Forty healthy middle aged men (50–65 years, BMI 25–29.9 kg/m²).

Measurements.?Changes in body weight (BW) and waist circumference (WC) were measured and body composition (BC), fat mass (FM), lean body mass (LBM) were measured by skin fold anthropometry at baseline and after 12 weeks of intervention. In addition, changes in physical fitness, metabolic and hormonal parameters (lipids, glucose, fructosamines, insulin, insulin-like growth factor-1, Leptin, human growth hormone, dehydroepiandrosterone, testosterone, hs-CRP, Il-6) were evaluated.

Results.?Thirty-five participants completed the 12 week study. No significant changes in BW were noted although RM and WC dropped and LBM increased after training, particularly in the RTS group (FM 22.6?±?5.5?kg to 21.2?±?4.7?kg; LBM 68.5?±?7.2?kg to 70.1?±?7.4; p?<?0.01). Subjects in the RTS group experienced more pronounced improvements in the strength measurements than the RT group. After the training intervention there were significant changes in hormonal and metabolic parameters as well as in glycemic control, particularly in the RTS group.

Conclusions.?Our data suggest that resistance training, particularly in combination with a soy protein based supplement improves body composition and metabolic function in middle aged untrained and moderately overweight males.     

Age-related variations in the growth hormone response to growth hormone secretagogues

Growth hormone (GH) secretagogues are synthetic peptidyl and non-peptidyl molecules which possess a strong, dose-dependent and reproducible GH-releasing effect after intravenous and even oral administration in humans. This effect is probably mediated via the activation of specific receptors, mainly present at the pituitary and hypothalamic level; a human pituitary GH secretogogue receptor has already been cloned, pointing to the existence of an endogenous GH secretagogue-like ligand. The GH-releasing effect of GH secretagogues is gender-independent but undergoes marked age-related variations. In fact, the effect is low at birth, increases markedly at puberty, persists at a similar level in adulthood and decreases thereafter, being already similar in middle age to that in elderly subjects. It is likely that the reduced activity of GH secretagogues in aging reflects the age-related changes in the neural control of somatotrope function. These could include the hypothetical impairment in the activity of the putative natural GH secretagogue-like ligand. Prolonged treatment with non-peptidyl GH secretagogues has been shown to restore spontaneous GH pulsatility and insulin-like growth factor I (IGF-I) levels in aged humans as well as in animals. The possibility that chronic treatment with GH secretagogues in aging rejuvenates the activity of the GH/IGF-I axis and counteracts the age-related changes in body composition, structure functions and metabolism seems very attractive.     

Hypogonadotrophic hypogonadism in type 2 diabetes

Recent work shows a high prevalence of low testosterone and inappropriately low luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity in patients with type 2 diabetes. However, the duration of diabetes or HbA1c are not related to HH. Furthermore, recent data show that HH is not associated with type 1 diabetes. C-reactive protein concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and C- reactive protein concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is also relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations are also related to an increase in total and regional adiposity. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates insulin resistance and inflammation. In addition, low testosterone levels are associated with an increase in cardiovascular events. Testosterone therapy may therefore, reduce cardiovascular risk. This important aspect requires further investigation.     

Is old age depressing? Growth trajectories and cohort variations in late-life depression

Findings in previous research on the association of old age and depression are inconsistent due to a confounding of age changes and cohort differences. Using data from an accelerated longitudinal design from the National Institute of Aging Established Populations for Epidemiologic Studies of the Elderly, this study addresses three questions: (1) Does the age growth trajectory show an increase in depressive symptoms in late life? (2) Is there cohort heterogeneity in levels of depressive symptoms and age growth trajectories of depressive symptoms? (3) What social risk factors are associated with these effects? Results show evidence of substantial cohort variation in depression. There is also evidence for an age-by-cohort interaction effect. Specifically, depression declined with age more rapidly for earlier cohorts. The growth trajectories can be accounted for by factors associated with historical trends in education, life course stages, health decline, differential survival, stress, and coping resources.     

Vitamin D and the postmenopausal population

Vitamin D, a hormone critical to the body's maintenance of serum calcium and phosphorus concentrations, is currently the subject of much scientific interest. Low levels of vitamin D have been observed in many populations and epidemiological studies have suggested a link between this biochemical state and a range of diseases, such as cancer, diabetes and multiple sclerosis. While the consequence of vitamin D deficiency is well documented for bone (rickets and osteomalacia), with mixed findings relating to falls and fractures, a causal link between vitamin D deficiency and these wider health outcomes has not been established. If these relationships were found to be causal, the morbidity and mortality resulting from low levels of vitamin D could be substantial; the current evidence base, however, most robustly supports the assessment of serum 25(OH)-vitamin D in the context of specific symptoms, low bone mineral density or biochemical abnormalities, rather than as an entity to treat in its own right or as the basis for a population-wide screening programme.     

Calcium and vitamin D--for whom and when

The basis of 'nutritional' interventions for the prevention of postmenopausal osteoporosis and osteoporotic fracture is a large topic with much genetic and biochemical evidence, as well as the results of randomized controlled trials, to guide the investigator and clinician. The efficacy of treatment with calcium and vitamin D was once controversial, but with the advent of controlled clinical trials using bone mineral density as an endpoint it has become clear that calcium with or without vitamin D therapy can lead to reductions in the rate of bone loss in postmenopausal women of all ages. Furthermore, with certain caveats, calcium with vitamin D therapy in the older postmenopausal woman can lead to useful reductions in fracture rates and falls, especially in populations with reduced exposure to sunlight, which is potentially the majority of postmenopausal women in both developed and developing countries. However, estrogen, selective estrogen receptor modulators (SERMs) and bisphosphonates (especially when given in combination with calcium and vitamin D) are more efficacious in preventing fracture, particularly in postmenopausal patients with impaired bone structure.     

Interdisciplinary technology assessment of service robots: the psychological/work science perspective

The article sheds light on psychological and work science aspects of the design and utilization of service robots. An initial presentation of the characteristics of man?Crobot interaction is followed by a discussion of the principles of the division of functions between human beings and robots in service area work systems. The following aspects are to be considered: (1) the organisation of societal work (such as the different employment and professional profiles of service employees), (2) the work tasks to be performed by humans and robots (such as handling, monitoring or decision-making tasks), (3) the possibilities and the limitations of realizing such tasks by means of information technology (depending, for example, on the motoric capabilities, perception and cognition of the robot). Consideration of these three design perspectives gives rise to criteria of usability. Current debate focuses on the (work science) principles of man?Cmachine communication, though in future these should be supplemented with robot-specific criteria such as "motoric capabilities" or "relationship quality." The article concludes by advocating the convergence and combination of work science criteria with ideas drawn from participative design approaches in the development and utilization of service robots.     

The insulin-like growth factor-I receptor: Implications for the aging process

Aging is associated with decreased levels of growth hormone and both circulating and local levels of insulin-like growth factor-I (IGF-I). The decline in IGF-I has been postulated to be important in both physiological aging and pathological states that are seen with aging. In parallel, inappropriate apoptosis is thought to play a role in some of these same processes. In experimental models, IGF-I signalling through the IGF-I receptor confers a protective effect from apoptosis. This review summarizes the results of studies documenting the IGF-I anti-apoptotic effect in neuronal model systems. The known downstream signalling cascades that mediate this signal are beginning to be elucidated; these include MAP kinase and Akt. In addition, IGF-I prevents the reduction of anti-apoptotic proteins of the bcl-2 family induced by hyperosmotic conditions in cultured neuronal cells. IGF-I has been shown to positively impact on tau, the microtubule-associated protein, possibly preventing the degradation of proteins that are associated with the neurofibrils seen in Alzheimer's disease. All of the studies to date support the hypothesis that appropriately high levels of IGF-I signalling prevent some of the processes associated with aging.     

Senility,illness and death in Açvaghosa's ‘Buddhacări˘ta’The Feats of Buddha

Background An age-related decline in growth hormone (GH) level has been established, and this decline is associated with changes in body composition as well as a general increase in susceptibility to illness and a reduced sense of well-being. The current study, a first in Asia, sought to examine the effects of GH therapy on body composition and other endocrine and metabolic functions in a group of healthy elderly Chinese men.

Methods A total of 23 healthy elderly Chinese men, aged between 60 and 69 years, were injected subcutaneously, three times weekly, with 0.08 U/kg of recombinant GH for 6 months. Various hormones and biochemical parameters, together with percentage lean body mass and body fat, were measured before, 3 and 6 months after the start and 3 months after the cessation of GH therapy.

Results A significant increase in lean body mass, up to 9.1% over baseline values at 3 months post-therapy, and a significant decrease in body fat, up to 3.1%, were noted. GH therapy also induced variable and significant increases in levels of insulin growth factor (IGF-I), dehydroepiandrosterone sulfate (DHEAS), insulin, triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) and triglyceride and significant reductions in glucose and sex hormone binding globulin (SHBG) levels. No changes in testosterone, free androgen index and cholesterol were noted. A significant and independent correlation was noted between IGF-I and insulin, TSH, DHEAS, glucose and triglyceride levels.

Conclusions GH augmentation therapy was effective in improving the body composition of a group of elderly Chinese men. GH-induced positive changes in body composition in the elderly were probably a result of the direct effect of the GH. It is also possible that some of the changes were mediated through GH-induced changes in thyroid hormones, insulin, glucose, triglyceride and DHEAS. However, the mechanism of GH- induced changes in body composition remains to be defined.     

Navigating terrains of violence: how South African male youngsters negotiate social change

Two concepts of separatism, embodied in the doctrines of Black Nationalism and Apartheid, have been advocated by sections of the Black minority in the United States and the White minority in South Africa. Although these ideologies have developed on diametrically opposed political foundations, situations of subordination in contrast to situations of dominance, they contain certain common themes. This paper explores a number of basic problems in the sociology of separatism: (i) what is distinctive about separatism as an ideology? (ii) what causes the emergence of specific separatist ideologies? (iii) what structural factors are common to both ‘dominant’ and ‘subordinate’ separatism? (iv) what are the manifest and latent functions of separatist ideologies? (v) what general sociological hypotheses can be drawn from these two case studies concerning the origin and persistence of separatist ideologies?