Recognising late-onset hypogonadism: a difficult task for sexual health care

Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterised by typical symptoms together with a deficiency in serum testosterone levels. Identification of LOH-related symptoms and signs is, therefore, essential for suspecting this condition. We investigated a specific association between indicative signs and symptoms of androgen deficiency and its biochemical correlates (total T below 12 and/or 8 nmol/l) in a large series (2817) of patients consulting our Sexual Dysfunction Unit. In addition, a systematic review of the literature using Medline (1969 to March 2009) was also performed. We found that although structured interviews, such as ANDROTEST or other self-reported questionnaires, might help physicians to familiarise themselves with hypogonadal symptoms and suspect LOH, LOH-related symptoms and signs are rather non-specific, as they are also characteristic of the ageing process per se. We confirmed that an accurate focused clinical history (inquiring about cryptorchidism, pituitary diseases and delayed puberty) can be very informative about the presence of LOH. In addition, sex life-related performances (libido, erection and ejaculation) and attitudes (masturbation and extra-marital affairs) might also provide insights. Clinical signs, such as testis volume, penile blood flow and the presence of the metabolic syndrome, can also raise the suspicion of LOH: an increased waist circumference increases the risk of having LOH by a factor of 3. Although a clinical evaluation is mandatory in suspecting LOH, it is our opinion that the determination of total testosterone is essential in confirming the diagnosis and/or in starting any substitutive therapy.     

Late-onset hypogonadism (LOH) and androgens: Validity of the measurement of free testosterone levels in the diagnostic criteria in Japan

The basis of diagnosis of late-onset hypogonadism (LOH) is the measurement of androgen levels. Traditionally, total testosterone (total T) was also used as the primary indicator of gonadal function in Japan. In 1998, the International Society for the Study of the Aging Male was founded to conduct basic and clinical research on this issue internationally. As a result, it is said that bioavailable testosterone levels should be measured in the diagnosis of LOH. At present, however, there are a number of problems for bioavailable testosterone to become a routine diagnostic tool. Here, we will explain the various measurement indicators of androgens, measurement problems, standard values of total T, and free testosterone (free T) in Japan, and the diagnostic methods for LOH overseas. In Japan, the Japanese Urological Association and the Japanese Association of Men's Health recommend the measurement of free T levels in the diagnosis of LOH, for the following reasons: (i) It has been demonstrated that free T is more strongly correlated with calculated bioavailable testosterone, than total T, showing a statistically significant difference; (ii) The behavior of free T is highly consistent with that of bioavailable testosterone, with free T levels being markedly decreased due to aging; (iii) For the measurement of free T, a method that allows the measurement of free T only, without affecting the balance between free T and protein-bound testosterone in blood, is available; and 4) The mean total T by age range decreases only to 80% of the young adult mean even during presenile and senile periods, when LOH occurs most frequently, but the free T level shows a linear decrease with aging and drops to 50% of the young adult mean. For these reasons, we will describe the validity of the recommendation for the measurement of free T levels.     

Survey for late-onset hypogonadism among old and middle-aged males in Shanghai communities

This study sought to investigate late-onset hypogonadism (LOH) in old and middle-aged males in Shanghai communities, using symptom score evaluation systems and measurements of sex hormone levels. One thousand cases of males aged 40-70 years were investigated. The aging male symptoms (AMS) scale and androgen deficiency in aging males (ADAM) questionnaire were used at the beginning of the investigation, followed by measurement of the sex hormone-related factors (total testosterone (TT), free testosterone (fT), sex hormone-binding globulin (SHBG) and bioavailability of testosterone (Bio-T)). There were 977 valid questionnaires. The LOH-positive rates shown by AMS and ADAM were 59.88% and 84.65%, respectively; values increased with the age of the patients. There were 946 results related to sex hormone measurements, which showed the following results: TT was not related to aging (P>0.05); levels of SHBG increased with age; and fT and Bio-T decreased with age. There was a significant difference in fT between LOH-positive and LOH-negative patients, as shown by the ADAM. In summary, TT levels were not related to aging, even though SHBG did increase while fT and Bio-T decreased with aging. Clinically, the diagnosis of LOH cannot be based on serum TT level.     

Diagnostik des „aging male“ — Was ist sinnvoll?

Aging is a complex process. In males after the 40th year of life the total serum testosterone (T) levels are decreased, especially the serum levels of so-called bioavailable testosterone (BT), whereas the serum levels of sex hormone binding globulin (SHBG) are increased. This androgen deficiency in males does not always cause symptoms.In symptomatic males a detailed history is required supported by screening questionnaires for androgen deficiency, followed by a clinical examination; the serum levels of T and SHBG should also be determined.In patients with normal serum levels of T and increased SHBG serum levels, free testosterone, obtained by calculation from the T and SHBG levels, is a reliable and simple index of BT to show the presence of androgen deficiency. Further endocrinological examinations are only recommended for differential diagnosis in the aging male.Before testosterone replacement therapy is started in symptomatic males with hypogonadism, risk factors, especially cancer of the prostate, have to be excluded.     

Challenges in the Diagnosis of the Right Patient for Testosterone Replacement Therapy

Diagnosis of testosterone deficiency is important to identify patients who might benefit from testosterone replacement therapy. Unfortunately, the diagnosis of hypogonadism may be a challenge for many practicing physicians, including endocrinologists and urologists. Signs and symptoms, such as sexual dysfunction, change in body composition, lethargy, and mood changes, are nonspecific and the available questionnaires are generally not useful in clinical practice. The diagnosis of testosterone deficiency is ultimately based on measurement of serum testosterone levels. However, marked variations in the reference ranges of serum testosterone levels among laboratories pose a challenge for physicians when interpreting the results. In addition, initial laboratory assessments usually determine total testosterone levels. About 1–2% of total testosterone is free and a further 30–50% is bound with low affinity to albumin; only these two components are bioavailable to the target tissues. In general, assuming the normal reference range for serum total testosterone in adult men is 300–1000 ng/dl (10–35 nmol/l), levels of < 250 ng/dl (8.7 nmol/l) suggest the patient is likely to be hypogonadal, whereas levels of > 350 ng/dl (12.7 nmol/l) suggest the symptoms may not be due to androgen deficiency. Values between 250 to 350 ng/dl warrant a repeat morning serum testosterone determination with assessment of free or bioavailable testosterone. In men with symptoms suggestive of androgen deficiency and borderline serum testosterone levels, where there are no contraindications to androgen therapy, a short therapeutic trial of testosterone may be justified.     

Testosterone replacement therapy for late-onset hypogonadism: current trends in Korea

Testosterone levels in men older than 40 years can decrease at a rate of 1%-2% per year, and reports show that more than 50% of 80-year-old men have testosterone levels consistent with hypogonadism. Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms of serum testosterone deficiency. In recent decades, the concept of LOH in ageing men has become familiar in European countries and the United States. It is also a topic of interest and debate throughout Korea. However, most of the data regarding advantages or disadvantages of testosterone replacement therapy (TRT) as treatment for LOH have been primarily obtained from studies on Western populations; therefore, studies of the effects of TRT in Asian men, who may have different serum testosterone compared to Western men, are needed. TRT is commonly prescribed in Korea, despite the paucity of studies on the effects of TRT in Asian populations. Data from various TRT studies based on Korean have shown its efficacy in increasing serum testosterone levels and improving subjective symptoms as assessed by questionnaires. Currently, patches and short-acting intramuscular injections are displaced by gels and long-acting formulations. However, to prevent overdiagnosis and overtreatment, indication for TRT should include both low testosterone levels and symptoms and signs of hypogonadism.     

Comparative study on evaluation methods for serum testosterone level for PADAM diagnosis

The International Society for the Study of the Aging Male (ISSAM) recommends that a diagnosis be based on a patient's total testosterone (TT), calculated free testosterone (cFT), or calculated bioavailable testosterone (cBT) for partial androgen deficiency of the aging male (PADAM). The purpose of this study was to confirm whether hypogonadism of patients with PADAM is related to symptoms and clarify which criteria of testosterone recommended by ISSAM is suitable for Japanese patients. A total of 90 patients with PADAM symptoms were included in this study. Endocrinologic profiles were reviewed as appropriate, and PADAM symptoms were judged by means of several questionnaires. Laboratory values and symptoms were compared between patients with and without hypogonadism. Even when any criterion of testosterone was used for diagnosis of hypogonadism, AMS (total and subscales), IIEF-5, or SDS scores of PADAM symptoms did not differ significantly between patients classified as having and not having hypogonadism. No other endocrinologic variables than testosterone differed significantly between them, either. PADAM symptoms are not related to testosterone level and it is still obscure whether ISSAM's criterion can be adopted for Japanese patients with PADAM. Other pathology needs to be addressed for evaluation and diagnosis of PADAM in Japan.     

Testosteronsubstitutionstherapie beim Prostatakarzinom

During the male 40s total testosterone levels decrease continuously. If clinical symptoms like decreasing libido, erectile dysfunction, osteoporosis, altered distribution of body fat, reduction in physical strength, or alterations in psychological mood are combined with a decreased serum testosterone level late-onset hypogonadism (LOH) is obvious. Before the substitution of testosterone is initiated, it is essential to exclude prostate cancer because the progress of prostate cancer depends on androgens. The question is now how to treat patients who suffer from androgen deficiency but have cured prostate cancer in their history? Concerning this there are only a few studies with a small number of patients which show that testosterone substitution therapy is possible without an increased risk for recurrence of prostate cancer. As long as the patient was cured it does not matter if he underwent a radical prostatectomy or brachytherapy. Absolutely necessary is that the patient is well informed about the therapy and regularly controlled during the therapy.     

Isolated ACTH deficiency in a late onset case of hypogonadism (LOH) not diagnosed by examination in an internal medicine clinic

We present a case of isolated adrenocorticotrophic hormone (ACTH) deficiency (IAD) in a late onset hypogonadism (LOH) clinic, not diagnosed by examinations in internal medicine. A 54-year-old man showed body weight loss with severe appetite loss, general malaise and hypotension. He visited our clinic for a checkup for LOH after general examinations in internal medicine. His hormonal examination showed undetectable ACTH and cortisol levels. However, the values of other pituitary hormones and testosterone were normal. A load test for anterior pituitary hormone (CRH + TRH + LHRH + GRH test) revealed that the ACTH-cortisol system showed no response although the other pituitary hormones responded. These findings confirmed the diagnosis of isolated ACTH deficiency. Administration of hydrocortisone dramatically improved his symptoms. Symptoms of IAD are similar to those of LOH syndrome and depression. Thus, we should consider IAD as one of the differential diagnoses in LOH clinics.     

Testosteronsubstitutionstherapie beim Prostatakarzinom

After the fourth decade of life the total testosterone level in men decreases continually. If clinical symptoms, such as decreased libido or erectile dysfunction are combined with a decreased serum testosterone level this is known as late onset hypogonadism (LOH) or partial androgen deficiency in the aging male (PADAM). In such cases testosterone substitution therapy is indicated. One important question is how to treat patients suffering from LOH but also have prostate cancer which was treated curatively in the past? Only relatively little data are available with small numbers of patients which show that testosterone substitution therapy is possible without an increased risk of a relapse in cases of cured prostate cancer. If the patient was cured it does not matter if radical prostatectomy or radiation therapy was used. It is mandatory that patients are well-informed about substitution therapy and that regular surveillance and controls are carried out during the therapy. For patients who still have prostate cancer which has not yet been treated or not yet cured decisions on whether the benefit of the testosterone replacement is greater than the potential risk of a progress of the disease have to be made on an individual case-specific basis.     

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males, but the mechanism remains unclear. In this study, we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity. Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production. In Leydig cells from young and aged rats, treatment with wortmannin, an autophagy inhibitor, inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production. In contrast, treatment with rapamycin, an autophagy activator, enhanced LH-stimulated steroidogenesis in Leydig cells from aged, but not young, rats. Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin. Furthermore, an increased level of ROS, induced by H(2)O(2), resulted in LH-stimulated steroidogenic inhibition. Finally, knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells, which were associated with increased intracellular ROS level. These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells, which might be influenced by intracellular ROS levels.     

Testosteron und erektile Dysfunktion

Primary hypogonadism represents a classic but rare cause of erectile dysfunction (ED) in men. Therapy with testosterone as monotherapy is therefore unlikely to cure ED in the typical ED patient. However, recent developments indicate a much greater role of testosterone in erectile function than has been supposed in the past. Serum testosterone levels decline in men with increasing age. Aging men might develop late-onset hypogonadism (LOH) associated with characteristic symptoms. Typical symptoms of LOH are represented by decreased libido and sexual function, osteoporosis, altered distribution of body fat, overall reduction in physical strength, and alterations in the general mood. Experimental and clinical studies over the last few years have also pointed out that hypogonadism results in characteristic alterations of the erectile tissue of the penis. These alterations might be reversible in response to hormone therapy with testosterone. Particularly testosterone might be a helpful supportive therapy in cases where PDE-5 antagonists have tended to lose their effectiveness on the erectile tissue in the treatment of ED.     

选择性雄激素受体调节剂（Sarm）对迟发性腺功能减退大鼠的作用研究

目的 通过观察选择性雄激素受体调节剂对迟发性腺功能减退大鼠的作用,为治疗LOH提供理论依据.方法 将30只符合标准的老年Wistar大鼠作为LOH动物模型,并随机分成3组：对照组（A）、DHT组（B）、Sarm组（C）,分别给予空白溶剂、雄激素及选择性雄激素受体调节剂（Sarm）进行干预,实验4周后观察各组大鼠LOH症状的改善情况并评分,检测血清游离睾酮的水平,计算前列腺相关指数.结果 干预4周后A、B、C三组大鼠LOH症状评分分别为（18.20±1.87）、（30.00±2.49）、（35.20±1.87）,血清游离睾酮分别为（2.248±0.305）、（1.088±0.258）、（2.526±0.283） pg/mL,前列腺指数分别为（0.321±0.008）％、（0.419±o.015）％、（0.304±0.007）％,各组间差异有统计学意义（P＜0.01）.结论 Sarm可能通过其与雄激素受体高度亲和力及选择性调节雄激素受体表达,明显改善LOH模型大鼠的LOH症状,有效抑制前列腺组织的增生,不影响自身睾酮的分泌.     

睾酮替代治疗雄激素缺乏ED患者65个月1例报告及文献复习

目的:通过对1例雄激素缺乏的ED患者行65个月的睾酮替代治疗观察,探讨长期睾酮替代治疗的可行性及雄激素缺乏ED的机制,为其合理治疗提供参考。方法:跟踪1例雄激素缺乏的ED患者应用睾酮替代治疗65个月的治疗效果、IIEF-5评分,雄激素变化,PSA、Hb及RBC变化及长期应用睾酮的不良反应监测,并结合相关文献进行分析。结果:46岁男性,IIEF评分7分,在未治疗前血清总睾酮(TT)2.79 ng/ml,反复多次应用多种PDE5抑制剂均无效,诊断为LOH,予以睾酮替代疗法,补充十一酸睾酮胶囊,开始2周80 mg,2次/日,后改为40 mg,2次/日,2个月后TT正常达3.45 ng/ml,体能、焦虑等症状明显好转,但是性功能无明显改善,予以PDE5抑制剂按需服用,感觉应用有效,IIEF评分21分,坚持联合用药45个月后停用PDE5抑制剂,单用睾酮替代治疗18个月,阴茎勃起坚挺,性功能满意,IIEF评分21分,定期复查性激素水平、PSA和血常规未见明显异常。结论:睾酮替代治疗可以改善PDE5抑制剂治疗雄激素缺乏的ED的效果,长期睾酮治疗雄激素缺乏症是安全、有效的。     

Correlations of androgen deficiency with clinical symptoms in Taiwanese males

The purpose of this study was to elucidate correlations between different biochemical measurements of androgen deficiency and clinical symptoms in male residents of Taiwan. An investigation of the serum biochemical markers for androgen deficiency in 650 males, including total testosterone, calculated free testosterone, and bioavailable testosterone, was conducted. Measurements of clinical symptoms were obtained using a questionnaire of the androgen deficiency in the aging male (ADAM) by St Louis University (SLQ). Correlations among the biochemical markers, correlations of the biochemical markers and age, and relationships between the biochemical markers and the SLQ were evaluated. The sensitivity and specificity of the SLQ were determined. Bioavailable and calculated free testosterone correlated better with age than did total testosterone. Eighty percent of the men had a positive SLQ, and 20% had a negative SLQ. The percentage of positive SLQ results increased with age. No statistically significant difference was noted between the biochemical markers of bioavailable and calculated free testosterone levels and the SLQ status except for men aged over 70 years. The SLQ in this study showed an acceptable sensitivity of about 80%, but the specificity was poor (about 20%). In conclusion, bioavailable testosterone and calculated free testosterone were more-closely correlated with age and may be better biochemical markers for androgen deficiency. SLQ might not be a suitable single measurement for androgen deficiency and should be used together with biochemical markers.     

Diagnosis and therapy of hypogonadism in adult males

Hypogonadism in men is defined as endocrine dysfunction of the testes, and due to reduced serum testosterone levels leads to symptoms of testosterone deficiency. Depending on the location of disruption in the endocrinological cycle, hypogonadism is classified as primary, secondary, or tertiary. In primary hypogonadism, the production of testosterone in the Leydig's cells of the testes does not function properly. Serum LH concentrations are elevated in the sense of counterregulation (hypogonadotropic hypogonadism). In secondary hypogonadism, LH secretion (and usually also FSH) from the hypophysis is impaired so that Leydig's cells are not stimulated, while in tertiary hypogonadism the hypothalamus is damaged. The clinical course in cases of reduced serum testosterone levels is determined essentially by the point in time when hypogonadism becomes manifest. Delayed puberty, eunuchoid stature, and underdeveloped secondary sex characteristics suggest prepubertal onset of hypogonadism.     

Prevalence of late-onset hypogonadism in men with type 2 diabetes mellitus

Late-onset hypogonadism (LOH) or age-associated testosterone deficiency syndrome is defined as a clinical and biochemical syndrome associated with advancing age and characterised by symptoms and a deficiency in serum testosterone levels. This condition may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. It has been suggested that sex steroid hormones may play a causal role in the development of insulin resistance and type II diabetes. This comparative study was aimed at determining the prevalence of LOH in diabetic men with erectile dysfunction and investigating the effect of testosterone replacement therapy on erectile function and on glycaemic control.     

Androgen deficiency and metabolic syndrome in men

Metabolic syndrome (MetS) is a growing health concern worldwide. Initially a point of interest in cardiovascular events, the cluster of HTN, obesity, dyslipidemia, and insulin resistance known as MetS has become associated with a variety of other disease processes, including androgen deficiency and late-onset hypogonadism (LOH). Men with MetS are at a higher risk of developing androgen deficiency, and routine screening of testosterone (T) is advised in this population. The pathophysiology of androgen deficiency in MetS is multifactorial, and consists of inflammatory, enzymatic, and endocrine derangements. Many options for the concomitant treatment of both disorders exist. Direct treatment of MetS, whether by diet, exercise, or surgery, may improve T levels. Conversely, testosterone replacement therapy (TRT) has been shown to improve MetS parameters in multiple randomized controlled trials (RTCs).     

浙江省一农村社区迟发性性腺功能减退症的调查研究

目的:调查乡村中老年男性迟发性性腺功能减退症(LOH)的流行病学情况。方法:2012年4～10月在浙江省嘉兴市嘉善县魏塘乡村采用年龄分层抽样选取996例40～80岁的中老年男性进行中老年男子雄激素缺乏(ADAM)、老年男子症状(AMS)和国际勃起功能问卷-5(IIEF-5)调查,同时测定血清中总睾酮(TT)、性激素结合球蛋白(SHBG)及白蛋白(ALB)水平,Vermeulen公式计算游离睾酮(cFT)及生物可利用睾酮(Bio-T)水平,超声检测前列腺、睾丸体积。结果:研究对象年龄(56.22±8.82)岁,ADAM及AMS筛查LOH的患病率分别为62.86%和23.05%;ED阳性率为68.83%,SHBG、LH、cFT及Bio-T筛查LOH各组之间存在统计学差异。结论:浙江省嘉善县魏塘乡村中老年男性LOH筛查率较国内其他报告(特别是大中城市)LOH筛查率低,ED患病率接近。城乡中老年LOH患病率有差别,值得进一步研究。     

Testosterone treatment of hypogonadal men participating in competitive sports

Testosterone has a steeply dose-dependent effect on muscle mass and strength irrespective of gonadal status. So, for reasons of fairness, people who engage in competitive sports should not administer exogenous testosterone raising their blood testosterone levels beyond the range of normal. There is a ban on exogenous androgens for men and women in sports, but an exception has been made for men with androgen deficiency due to pituitary or testicular disease. Men who receive testosterone administration for the indication hypogonadism have an interest in the use of testosterone preparations generating blood testosterone levels within the normal range of healthy, eugonadal men. On the grounds of a positive correlation between blood testosterone concentrations muscle and volume/strength, they are best served with a parenteral testosterone preparation, rather than transdermal testosterone, but they should not run the risk of being excluded from competition because of supraphysiological testosterone levels. The latter is a realistic risk with the traditional parenteral testosterone esters. The new parenteral testosterone undecanoate preparation offers much better perspectives. Its pharmacokinetics have been investigated in detail and there is a fair degree of predictability of resulting blood testosterone levels with use of this preparation.