十一酸睾酮治疗迟发性性腺功能低下的研究进展

随着老年化社会的到来,迟发性性腺功能低下的患者人数也逐渐增加。治疗迟发性性腺功能低下的方法也多种多样,而十一酸睾酮作为治疗迟发性性腺功能低下的主要药物,获得明显效果。本文就十一酸睾酮治疗迟发性性腺功能低下的研究进展作一综述。     

Is discontinuation of hormone replacement therapy possible for patients with late‐onset hypogonadism?

Objective:   The first-line treatment for late-onset hypogonadism (LOH) is hormone replacement therapy (HRT). However, whether lifetime HRT is necessary has not been settled. We evaluated LOH-related symptoms and endocrinologic values after discontinuation of HRT in patients with LOH who had benefited from it.
Methods:   Twenty-five men (mean age 54.2 years, range 40–73) in whom HRT had been effective and who were available for follow-up 3 months after the discontinuation of HRT were studied. LOH-related symptoms were judged according to the Aging Males' Symptoms (AMS) scale and other questionnaires. Laboratory and endocrinologic values and LOH-related symptoms were assessed before HRT, at the end of HRT, and 3 months after its discontinuation.
Results:   Serum testosterone levels increased significantly with HRT. However, they returned to the pretreatment levels after discontinuation of HRT. The total AMS score decreased significantly after HRT, and a significant improvement was maintained 3 months after discontinuation. The somatovegetative and psychological subscores of the AMS also improved, although the sexual subscore did not change significantly. A slight improvement was also observed in the short version of the International Index of Erectile Function (IIEF-5) score and the Self-rating Depression Scale (SDS) score after HRT. However, changes in these scores did not reach statistical significance. No other changes in the endocrinologic profile and no severe adverse effects were seen.
Conclusions:   Improvement in symptoms may remain after discontinuation of HRT in patients with LOH even though their endocrinologic status declines. Our findings may encourage physicians to discontinue HRT if LOH-related symptoms have improved after several months of HRT.     

Treatment for late-onset hypogonadism: the current situation in Japan

Prevention of age-related disability has become very important because the number of people aged 60 years and older is increasing rapidly. Androgen levels decrease with aging and this plays many physiologic roles in various organs. Late-onset hypogonadism (LOH) has received widespread attention in the last few years. LOH symptoms include sexual dysfunction and depression, and the first-line treatment should be hormone replacement therapy (HRT), by which several symptoms of LOH are improved. Although several types of testosterone preparations are available worldwide, the testosterone preparations available in Japan are limited. For this reason, the Clinical Practice Manual for LOH, authored by a collaborative team from the Japanese Urological Association and the Japanese Society for the Study of the Aging Male, recommends HRT with testosterone enanthate, human chorionic gonadotropin (hCG) and ‘Glowmin’, a short-acting testosterone ointment produced in Japan. In this review, we summarize the efficacy of HRT for LOH symptoms and introduce hCG and Glowmin therapy according to the Clinical Practice Manual. However, several studies, including our own, have shown that LOH symptoms are not always related to serum testosterone concentration. Thus, HRT is not adequate as the only treatment option for LOH because eugonadal men with symptoms of LOH comprise 30% of the general population. We discuss the efficacy of Japanese herbal medicines, which have been used for treatment of the menopause and several psychological disorders, particularly in the treatment of eugonadal patients with symptoms of LOH.     

Testosterone replacement therapy for late-onset hypogonadism

Cross-sectional and longitudinal studies have shown that testosterone levels fall with increasing age. Low testosterone levels are reported in 20% of men aged 60-69 years, and 30% of men in this age-group are thought to have low free testosterone levels. The prevalence of low testosterone levels increases in older men and, therefore, as the average age of men in developed countries is increasing, there will be even more hypogonadal men in the future. Many of the symptoms and signs associated with testosterone deficiency in younger men are present in aging men. Several small studies suggest that testosterone replacement therapy (TRT) can be beneficial for some aging men, but men in these studies have not been uniformly testosterone-deficient, and responses have been inconsistent. TRT might be more beneficial and safer in men aged below 65 years than in men aged 65 years or older. There is a need for large clinical trials in both age-groups to provide more definitive information for patients and clinicians as to the safety and efficacy of TRT. Before such data are available, clinicians must be cautious in offering these treatments to aging men. Close monitoring of patients undergoing testosterone supplementation is essential.     

Testosterone replacement therapy in older adult men

Serum testosterone levels decline slowly with normal ageing in men and, although all men are not destined to become hypogonadal as they age, the prevalence of androgen deficiency in the older male is not insignificant. Over the past several decades, there has been an increasing interest in evaluating whether testosterone therapy (male HRT) might be beneficial for certain older men in preventing or reversing some aspects of ageing. The major androgen target organs of interest with regard to beneficial effects of male HRT include bone, muscle, adipose tissue, the cardiovascular system and the central nervous system (libido and aspects of mood). At the same time, potential adverse effects of male HRT on target organs such as the prostate continue to be evaluated. It is the purpose of this review to summarize the information to date with regard to testosterone replacement therapy in the older man and to discuss areas where more research and clinical information need to be forthcoming. Hormonal replacement therapy (HRT) for post-menopausal women has been studied and discussed for many years. The idea of male HRT, however, is a relatively recent development, with increasing interest in this area occurring only over the past two decades. Reasons for this nascent enthusiasm include burgeoning evidence that testosterone levels decline with normal male ageing (and with age-associated diseases) and an interest in preventing age-related dysfunction and prolonging quality life among an ever increasing population of older adults. The decline in testosterone with age often parallels unfavourable changes in organs upon which androgens act and the goal of male HRT would be to prevent, stabilize or even reverse some of these detrimental target-organ changes.     

Distribution of Testosterone in Plasma Proteins during Replacement Therapy with Testosterone Enanthate in Patients Suffering from Hypogonadism*

Verteilung des Testosterons zwischen den Plasmaproteinen während einer Substitutionstherapie mit Testosteronenenthate bei hypogonadalen Männern Bei fünf hypogonadalen Männern, die mit 250 mg Testosteronenanthate alle 3 Wochen behandelt wurden, bestimmten wir im Plasma das Gesamttestosteron, das ?freie” Testossteron sowie die prozentuale Verteilung des Testosterons zwischen dem sexsteroidbindenden Globulin und dem Albumin über einen Zeitraum von 3 Wochen. Unmittelbar nach der Testosteroninjektion stieg das Gesamttestosteron rasch auf den vierfachen Wert des Ausgangsspiegels an, wobei das ?freie” Testosteron einen parallelen Kurvenverlauf zeigte. Wir fanden, daß wenn die Kapazität des sexsteroidbindenden Globulins überschritten wird, Albumin den Testosteronüberschuß bindet. Während in der ersten und zweiten Woche nach der Injektion hohe bzw. ausreichende Testosteronspiegel gewährleistet sind, nähert sich das Gesamttestosteron in der dritten Woche dem unteren Normbereich für Männer von 300 ng/dl bzw. das ?freie” Testosteron von 5 ng/dl. Bei einem Patienten mit einer Hypalbuminämie konnte das Albumin diese Transportfunktion nur ungenügend übernehmen. Obwohl bei ihm in der dritten Behandlungswoche der Spiegel des Gesamttestosterons noch ausreichend war, fanden sich sehr niedrige Werte von ?freiem” Testosteron unter 3 ng/dl. Im Einklang damit klagte er über Androgenman-gelsymptome. Wir folgern daraus, daß durch Verteilungsstörungen des Androgens zwischen den Plasmaproteinen ein Defizit des ?freien” Testosterons auftreten kann, obwohl das Gesamttestosteron noch einen ausreichenden Plasmaspiegel aufweist.     

Testosterone replacement therapy in male hypogonadism is not associated with increase of endothelin-1 levels

Differences in endothelin-1 (ET-1) blood plasma levels were established between healthy men and women. Little is known about vascular effects of testosterone and the interactions between sex hormones and endothelin. In order to study the relationship between ET-1 and testosterone in more detail, we have investigated 33 male patients with various forms of hypogonadism (13 with hypergonadotropic hypogonadism and 20 with hypogonadotropic hypogonadism). Fourteen age-matched healthy males served as controls. The basal ET-1 levels in patients with hypogonadism (0.96 +/- 0.12 fmol/mL) (mean +/- SEM) were significantly higher in comparison with the controls (0.44 +/- 0.04 fmol/mL), p < 0.01. Fifteen individuals of these patients were studied during the therapy with testosterone depot 250 mg i.m. The ET-1 levels decreased in this group from 0.99 +/- 0.22 to 0.78 +/- 0.14 fmol/mL at the third and to 0.76 +/- 0.25 fmol/mL at the sixth month of the medication, respectively. The differences were not significant compared with the initial levels, but the concentrations at the sixth month of the treatment were not statistically different in comparison with the ET-1 levels of the controls. There was no significant difference in lipid data between patients before and during testosterone medication, except for the high-density lipoprotein cholesterol, which decreased at the third month of the treatment. Our results show that plasma ET-1 levels in males with hypogonadism are elevated with a tendency to decrease after testosterone administration. The optimum testosterone is not associated with enhanced cardiovascular risk as far as ET-1 plasma levels and lipids are concerned.     

Late-onset hypogonadism: beyond testosterone

Late-onset hypogonadism is defined as a combination of low testosterone (T) levels and typical symptoms and signs. A major area of uncertainty is whether T concentrations are always really sufficient to fully reflect Leydig cell (dys)function. Mild testicular alteration could be diagnosed only by additional biochemical markers, such as luteinizing hormone (LH) and 25-hydroxyvitamin D levels. These markers help in identifying the so-called “subclinical” hypogonadism (normal T, high LH levels). Patients with hypogonadism have frequently low levels of 25-hydroxyvitamin D due to impairment of the hydroxylating enzyme CYP2R1 in the testis. However, no data have been published dealing with the best treatment option (cholecalciferol – the Vitamin D precursor, or calcidiol - 25-hydroxylated form of Vitamin D) in these patients. We studied 66 patients with classic hypogonadism (total T [TT] <12 nmol l⁻¹, LH ≥ 8 IU l⁻¹) (n = 26) and subclinical hypogonadism (TT ≥ 12 nmol l⁻¹, LH ≥ 8 IU l⁻¹) (n = 40) and low 25-hydroxyvitamin D (<50 nmol l⁻¹). Subjects received cholecalciferol (5000 IU per week) (n = 20) or calcidiol (4000 IU per week) (n = 46), and 25-hydroxyvitamin D and parathyroid hormone (PTH) were evaluated after 3 months of therapy. Supplementation with calcidiol significantly increased 25-hydroxyvitamin D and significantly decreased PTH levels in both groups of men with hypogonadism (primary, n = 16 and subclinical, n = 30), whereas supplementation with cholecalciferol did not modify their levels. This study shows for the first time that the administration of the 25-hydroxylated form of Vitamin D (calcidiol), and not the administration of the precursor cholecalciferol, restores 25-hydroxyvitamin D levels in subjects with hypogonadism.     

Testosterone therapy in men with prostate cancer: literature review,clinical experience,and recommendations

For several decades any diagnosis of prostate cancer (PCa) has been considered an absolute contraindication to the use of testosterone (T) therapy in men. Yet this prohibition against T therapy has undergone recent re-examination with refinement of our understanding of the biology of androgens and PCa, and increased appreciation of the benefits of T therapy. A reassuringly low rate of negative outcomes has been reported with T therapy after radical prostatectomy (RP), radiation treatments, and in men on active surveillance. Although the number of these published reports are few and the total number of treated men is low, these experiences do provide a basis for consideration of T therapy in selected men with PCa. For clinicians considering offering this treatment, we recommend first selecting patients with low grade cancers and undetectable prostate-specific antigen following RP. Further research is required to define the safety of T therapy in men with PCa. However, many patients symptomatic from T deficiency are willing to accept the potential risk of PCa progression or recurrence in return for the opportunity to live a fuller and happier life with T therapy.     

Assessment of possible effects for testosterone replacement therapy in men with symptomatic late-onset hypogonadism

We herein report clinical assessments of efficacy and side effects of T replacement therapy (TRT) in men with late-onset hypogonadism (LOH). The study included 56 patients who were diagnosed with LOH and treated with TRT for at least 6 months at our institution. Age, ageing male symptom (AMS) scale, and androgen decline in the ageing male (ADAM) questionnaires were examined. Fasting blood samples were analysed for sex hormones, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), red blood cell count (RBC), haemoglobin (Hb), haematocrit (Ht), and prostate-specific antigen (PSA). Total and psychological symptoms scores were measured by the AMS scale and the ADAM questionnaire score, demonstrating that the sum of positive responses to the questions were significantly improved after TRT (P < 0.05). TC, HDL, and LDL cholesterol, TG, AST, ALT, γ-GTP, RBC, Hb, Ht, and PSA were not significantly different between before and after TRT. Although TRT for men with LOH may cause favorable changes in psychological conditions, it may not have effects on lipid metabolism, liver function, RBC, and PSA level.     

Effects of long-term testosterone substitutive therapy on bone mineral content in men with hypergonadotrophic hypogonadism

Hypogonadism is one of the crucial risk factors for male osteopenia and osteoporosis. There are few studies on the effects of long-term and consistently administered testosterone substitutive therapy on bone mineral density in men with gonadal androgen deficiency, and their results have been susceptible to various interpretations. The aim of our study was an evaluation of bone mineral content in 26 men, aged 18-57 years, with hypergonadotrophic hypogonadism who underwent long-lasting androgen re-placement therapy with testosterone esters (Omnadren 250), which conditioned proper psychosomatic androgenization. The control group comprised 405 healthy men, aged 20-60 years, a representative sample of the local male population. Among all examined men and in the control group, trabecular, cortical and total bone mineral content at the distal radius of the nondominant hand were assessed by peripheral quantitative computed tomography using the Stratec 960 apparatus. In 11 hypogonadal men (42.3%), the trabecular bone mineral content was found to be within normal ranges; in 15 patients (57.7%) its values were below -1 standard deviation (SD) (osteopenia). In six patients (23.1%), the cortical bone mineral content was between +1 SD and the arithmetic mean, X; in 13 examined men (50%), the cortical bone mineral content was below X and above -1 SD. Osteopenia was diagnosed in six hypogonadal males, whereas osteoporosis was found in one man (cortical bone mineral content below -2.5 SD). Only in seven of the examined men (26.9%) was the total bone mineral content found within normal ranges, whereas in 19 men (73.1%) the total bone mineral content was below -1 SD (osteopenia). Despite the testosterone replacement in hypogonadal men, the greatest reduction of bone mineral content was found in its trabecular and total values. Among all the men examined, the trabecular and total bone mineral contents were below the mean of our own reference values. The results show that long-term and consecutively administered testosterone replacement in conventional doses, despite the normalization of serum androgen levels and the promotion of proper somatic development, does not simultaneously eliminate hypogonadal osteopenia in every case. The individually differentiated response to exogenous androgens is a characteristic feature of male hypogonadism. This study emphasizes the necessity of regular measurements of bone mineral density in hypogonadal men, as the densitometric parameters should be accepted as an osteologic (and very important) marker of androgenization of the male organism.     

Testosterone replacement therapy improves health‐related quality of life for patients with late‐onset hypogonadism: a meta‐analysis of randomized controlled trials

Although testosterone replacement therapy can restore serum testosterone concentrations to normal level in late‐onset hypogonadism patients, whether it can improve patients' quality of life remains uncertain. Therefore, we perform a meta‐analysis of randomized controlled trials on this issue. Five randomized controlled trials total 1,212 patients were included. Fixed‐effect model was used to calculate the weighted mean difference of score of Aging Males' Symptom rating scale. Our result reveals that testosterone replacement therapy improves patients' health‐related quality of life in terms of the decrease in the AMS total score [WMD = ?2.96 (?4.21, ?1.71), p < .00001] and the psychological [WMD = ?0.89 (?1.41, ?0.37), p = .0008], somatic [WMD = ?0.89 (?1.41, ?0.37), p = .0008] and sexual [WMD = ?1.29 (?1.75, ?0.83), p < .00001] subscale score.     

Prospective assessment of health‐related quality of life in men with late‐onset hypogonadism who received testosterone replacement therapy

The objective of this study was to characterise the status of health‐related quality of life (HRQOL) in Japanese men with late‐onset hypogonadism (LOH) treated with testosterone replacement therapy (TRT). HRQOL in 69 consecutive Japanese men with LOH undergoing TRT for at least 6 months was prospectively evaluated before and 6 months after the initiation of TRT using the Medical Outcomes Study 8‐Item Short‐Form Health Survey (SF‐8). All eight‐scale scores except for bodily pain (BP) in the 69 patients at 6 months after the introduction of TRT significantly improved compared with those before TRT; however, all scale scores except for BP in the 69 patients were significantly inferior to those in age‐matched Japanese controls irrespective of the timing of SF‐8. Multivariate analyses of several parameters revealed that both age and Aging Male Symptom (AMS) score had an independent impact on mental health (MH), despite the lack of an independent association between any score and the remaining factors examined. TRT appeared to significantly improve the status of HRQOL in men with LOH; however, even after the introduction of TRT, HRQOL associated with MH remained significantly impaired in elderly men and/or those with a high AMS score.     

Effects of testosterone replacement therapy on metabolic syndrome among Japanese hypogonadal men: A subanalysis of a prospective randomised controlled trial (EARTH study)

We investigated the effects of testosterone replacement therapy (TRT) on metabolic factors among hypogonadal men with a metabolic syndrome. From the study population of the EARTH study, which was a randomised controlled study in Japan, 65 hypogonadal patients with a metabolic syndrome, comprising the TRT group (n = 32) and controls (n = 33), were included in this study analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 12 months. Waist circumference, body mass index, body fat volume and blood pressure were measured in all patients at baseline and at 12 months. In addition, blood biochemical data, including total cholesterol, triglyceride (TG), HDL cholesterol, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) levels, were also evaluated. Changes in these categories from baseline to 12 months were compared between the TRT and control groups, with significant differences observed in waist circumference, body fat percentage, FPG, TG and HbA1c levels. No significant differences were observed in other parameters. TRT for 1 year was associated with improvements in some metabolic factors among Japanese men with hypogonadism and metabolic syndrome.     

他达拉非对中老年男性LOH患者T、IIEF及SEP影响的临床研究

目的:观察他达拉非联合安特尔治疗中老年男性迟发性性腺功能低下(LOH)的临床疗效。方法:选择125例中老年男性LOH患者随机分为两组,治疗组65例使用他达拉非加十一酸睾酮治疗,对照组60例使用十一酸睾酮胶囊治疗。分别记录治疗前及治疗后4周时的总睾酮(T)、国际勃起功能指数评分(IIEF)、患者性生活日记(SEP)等的变化。结果:治疗后2组T、IIEF及SEP评分均有不同程度改善,与治疗前比较,差异均有统计学意义(P<0.05);治疗组T、IIEF及SEP评分改善更为显著,与对照组比较,差异均有统计学意义(P<0.05)。结论:使用他达拉非联合十一酸睾酮胶囊,可较好地改善中老年男性患者T、IIEF及SEP分数,提高患者性生活满意度及自信心,具有比单纯补充睾酮更好的综合疗效。     

Adiponectin and testosterone in patients with symptoms of late‐onset hypogonadism: Is there a link?

Objectives:   To examine the correlation between testosterone and adiponectin in symptomatic late-onset hypogonadism (LOH) patients.
Methods:   The study included 174 patients (>40 years old) with at least one LOH symptom and an Aging Male Symptoms score >26. The correlation between serum adiponectin levels and various factors was investigated by simple and multiple regression analyses. Serum adiponectin levels before and after testosterone replacement therapy (TRT) in 43 patients with serum free testosterone <11.8 pg/mL were also compared.
Results:   Serum adiponectin levels increased with increased age ( P  < 0.01), decreased with increased body mass index ( P  < 0.01), and increased with increased sex hormone-binding globulin ( P  < 0.01). Multiple regression analysis revealed that body mass index and sex hormone-binding globulin were factors with an influence on serum adiponectin levels. However, no association between testosterone and adiponectin was found. In the 43 patients receiving TRT, serum adiponectin levels before and after TRT did not differ significantly.
Conclusions:   Serum adiponectin is not related to serum testosterone in symptomatic LOH patients, suggesting that TRT in these subjects does not pose a higher risk of inducing a metabolic syndrome.     

老年男性勃起功能及迟发性性腺功能减退症状与下尿路症状严重性的关系

本文旨在研究土耳其爱琴海地区的老年男性下尿路症状（LUTSs）、勃起功能障碍（ED）和有症状的迟发性性腺功能减退症（SLOH）三者间的关系。符合以下标准的500名男性患者被纳入该研究：40周岁以上;过去6个月内有稳定的性关系;在六个泌尿外科诊所之一进行过就诊登记。每位患者均行血清PSA、睾酮水平及尿流率的检测,并填写国际前列腺症状评分和生活质量评分（IPSS-QoL）量表、国际勃起功能指数（IIEF）问卷和老年男性症状（AMS）量表。在所有的研究对象中,23．9％的患者有轻度LUTSs,53．3％有中度LUTSS,22．8％有重度LUTSS。每组间总睾酮水平无明显差异。除此之外,69．6％的病人患有ED,且ED的发生率与LUTS严重性呈正相关。71．2％的患者出现SLOH（AMS〉27）,且IPSS评分越高,严重的性腺功能减退症状的发生率也越高。相关性分析显示以上三种问卷分数之间有显著关联。总之,LUTS严重性是ED和SLOH的非年龄依赖性危险因素,LUTS严重性和SLOH症状之间似乎有显著的相关性,但还需要从病因学和生物学角度进行深入阐明。