The polymorphic androgen receptor gene CAG repeat,pituitary-testicular function and andropausal symptoms in ageing men

The activity of androgen receptor (AR) is modulated by a polymorphic CAG trinucleotide repeat in the AR gene. In the present study, we investigated hormonal changes among ageing men, and whether the number of AR CAG triplets is related to the appearance of these changes, as well as symptoms and diseases associated with ageing. A total of 213 41-70-year-old men donated blood for hormone analyses (LH, testosterone, oestradiol and SHBG) and answered questions concerning diseases and symptoms associated with ageing and/or androgen deficiency. Of these men, 172 donated blood for the measurement of the CAG repeat length of AR. The CAG repeat region of the AR gene was amplified by polymerase chain reaction (PCR) and the products were sized on polyacrylamide gels. The repeat number was analysed as a dichotomized variable divided according to cut-off limits of the lowest (< or =20 repeats) and the highest quartile (> or =23 repeats), and as a continuous variable. The proportion of men with serum LH in the uppermost quartile (>6.0 IU/L) with normal serum testosterone (>9.8 nmol/L, above the lowest 10%) increased significantly with age (p = 0.01). There were fewer men with this hormonal condition among those with CAG repeat number in the uppermost quartile (> or =23 repeats) (p = 0.03). These men also reported less decreased potency (p < 0.05). The repeat number was positively correlated with depression, as expressed by the wish to be dead (r = 0.45; p < 0.0001), depressed mood (r = 0.23; p = 0.003), anxiety (r = 0.15; p < 0.05), deterioration of general well-being (r = 0.22; p = 0.004), as well as decreased beard growth (r = 0.49; p < 0.0001). A hormonal condition where serum testosterone is normal but LH increased is a frequent finding in male ageing. Only certain types of age-related changes in ageing men were associated with the length of the AR gene CAG repeat, suggesting that this parameter may play a role in setting different thresholds for the array of androgen actions in the male.     

雄激素部分缺乏误诊为中老年抑郁和痴呆1例

中老年男性出现一系列雄激素部分缺乏的临床症状特别容易与抑郁和痴呆相互混淆,并因此而造成误诊误治。本文报道了1例中老年男性雄激素部分缺乏综合征(PADAM)患者反复被误诊为老年抑郁和痴呆,值得引起临床关注。造成误诊误治的原因主要包括对PADAM的含义不了解、临床症状缺乏特异性、没有进行必要的专科检查和激素水平分析等。     

Androgens and the ageing male

Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men with severe primary or secondary hypogonadism. Thus, androgen substitution therapy is warranted in men with true hypogonadism at all ages. Symptoms experienced by otherwise healthy ageing males are non-specific and vague, although some may be similar to symptoms of hypogonadism. Therefore, the term 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial in some elderly males with low-normal testosterone levels. However, at this point in time, widespread use of testosterone in an elderly male population outside controlled clinical trials seems inappropriate.     

ANDROPAUSE: ENDOCRINOLOGY,ERECTILE DYSFUNCTION,AND PROSTATE PATHOPHYSIOLOGY

This review summarizes major biological aspects of andrology of andropause, deficiency in androgens/growth hormones, and molecular parameters; erectile dysfunction (ED), the use of malleable, mechanical, inflatable devices as well as the application of Viagra (Sildenafil), alprotadil (Caverject), Yohimbine, and other drugs not yet approved by FDA, such as Papaverine, phentolamine (Vasomax), and apormorphine (Uprima); osteopenia/osteoporosis: testosterone/osteoporesis; supplementation during andropause: administration of andiogens, possible risk factors of androgens, calcium supplement and muscle mass; prostate pathophysiology: consequences of prostatectomy, prostate cancer, benign prostatic hyperplasia (BPH), hormone–dependent cancers; bladder and urethral dysfunction: neurological parameter, urodynamics technology; models on aging in male animals: comparative physiology of prostate of laboratory animals/farm animals; future research: functional anatomy of male reproductive organs, pharmacokinetics of osteoporosis, endocrinology/neuroendocrinology/chromosome anomalies supplementation during andropause, experimental animal models and future multicenter multidisciplinary research.     

唾液游离睾酮测定的临床应用

借鉴国内外文献报告的方法，建立了唾液游离睾酮的测定方法，可替代血游离睾酮的测定。本法批内变异系数５．７５％，批间变异系数８．４５％，提取回收率９４％，最小检出量（灵敏度）１２．３０ｐｇ（９５％可信限）。唾液游离睾酮与血清总睾酮之间有极好的相关性（ｒ＝０．９８４，Ｐ＜０．００１）。唾液游离睾酮测定方法实用、可靠，在临床应用中取得满意结果，加之取材容易，病人易于接受，具有很好的社会和经济效益。     

Testosterone levels in men with erectile dysfunction

OBJECTIVE: To investigate the frequency of hypogonadism in men with erectile dysfunction (ED) and to assess which factors are related with low testosterone levels. PATIENTS AND METHODS: In all, 165 men with ED were assessed; the evaluation included: hormonal profiles, serum total and free testosterone (using Vermeulen's formula) levels, and self-reported questionnaires on erectile function and desire domains of the International Index of Erectile Function. The frequency of hypogonadism was established using total and free testosterone levels as diagnostic criteria. The factors that might influence testosterone levels were evaluated by univariate and multivariate statistical analysis, and a logistic regression was used to determine which factors can predict free testosterone levels below normal limits (biochemical hypogonadism). RESULTS: Using the total testosterone levels, 4.8% of the men were hypogonadal, whereas when using the free testosterone levels, 17.6% were hypogonadal. In the univariate analyses, not smoking and hypertension were associated with lower total and free testosterone levels. Ageing, absence of nocturnal erections and a lower erectile function score were only associated with lower free testosterone serum levels. There was no association between total and free testosterone levels and desire. In the multivariate analysis, only total testosterone levels were related to hypertension, while free testosterone levels were related to age and nocturnal erections. For biochemical hypogonadism, simple logistic regression analysis selected age, erectile function score and aetiological diagnosis of ED as predictors. In the multivariate analysis only the erectile function score had significant independent prognostic value. CONCLUSIONS: The frequency of hypogonadism is higher when free testosterone levels are used for diagnosis. The total and free testosterone levels were not related to the level of sexual desire in men with ED. The free testosterone levels could be related to the quality and frequency of nocturnal erections, and when ED is more severe, it is more probable that free testosterone levels are below the 'normal' limit.     

Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism

Clinical studies suggest there may be a threshold concentration of serum testosterone below which replacement will result in skeletal and psychological benefit. We evaluated the response to testosterone in men with borderline hypogonadism. A randomized double-blind placebo-controlled trial in 39 men over age 40 years presenting with sexual dysfunction and a borderline low testosterone level (total testosterone <10 nmol/L or free androgen index <30%). Patients were randomized to Testoderm TTS body patch (5 mg/day, n = 20) or a placebo patch (n = 19) for 6 months, followed by open-label testosterone replacement for a further 6 months in all patients. During the placebo-controlled phase of the study serum testosterone increased significantly on testosterone vs. placebo treatment (p = 0.004); this was associated with a decrease in total body fat mass (p = 0.019) and increase in haemoglobin level (p = 0.036). There were no significant changes in lean body mass, markers of bone turnover, and measures of bone mineral density (BMD). There was evidence of difference in quality of life according to the Male Erectile Dysfunction Quality of Life questionnaire (MEDQoL score, p = 0.017), mainly accounted for by deterioration in the placebo arm. When the active treatment period was combined for placebo and testosterone groups, the within-patient analysis showed a significant effect of testosterone to decrease markers of bone resorption (uNTX/Cr, p = 0.007; iFDPD/Cr, p = 0.0006) and to increase lean body mass (p = 0.001). There was little convincing evidence from this study that testosterone replacement is likely to have major benefit in men over age 40 years with borderline hypogonadism and sexual dysfunction. However, there was evidence of suppression in bone resorption and hence longer and larger studies are needed to examine its effect on BMD.     

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.     

Andropause and the development of cardiovascular disease presentation—more than an epi-phenomenon

Andropause refers to a generalized decline of male hormones, including testosterone and dehydroepiandrosterone in middle-aged and aging men. This decline in hormones has been associated with changes such as depression, loss of libido, sexual dysfunction, and changes in body composition. Aging has been associated with an abundance of concomitant diseases, in particular cardiovascular diseases, and although andropause is correlated to aging, a causal relationship between reduction of androgens and the development of chronic diseases such as atherosclerosis and heart failure has not been convincingly established yet. On the other hand, increasing data has emerged that revealed the effects of low levels of androgens on cardiovascular disease progression. As an example, low levels of testosterone have been linked to a higher incidence of coronary artery disease. Whether hormone replacement therapy that is used for andropausal men to alleviate symptoms of “male menopause” can halt progression of cardiovascular disease, remains controversially discussed, primarily due to the lack of well-designed, randomized controlled trials. At least for symptom improvement, the use of androgen replacement therapy in andropausal men may be clinically indicated, and with the appropriate supervision and follow up may prove to be beneficial with regard to preservation of the integrity of cardiovascular health at higher ages.