Recommendations on the diagnosis,treatment and monitoring of late-onset hypogonadism in men – a suggested update

Abstract

Recommendations on the diagnosis, treatment and monitoring of late-onset hypogonadism (LOH) in men were first published by ISSAM in 2002 In 2005, and, in 2008, updated recommendations were published in the International Journal of Andrology, the Journal of Andrology, the Aging Male and European Urology. Towards discussions at the next ISSAM/ESSAM meeting in Moscow, 29 November 2013, we suggest the following update.     

Comprehensive evaluation of androgen replacement therapy in aging Japanese men with late-onset hypogonadism

Abstract

Objective: This study assessed the efficacy and safety of testosterone replacement therapy (TRT) in aging Japanese men with late-onset hypogonadism (LOH).

Methods: This study included 50 (median age: 57.7 years) Japanese men with LOH, who were consecutively enrolled and treated with TRT for at least six months at our institution. We evaluated the following measurements before and after six months of treatment with TRT as follows: blood tests, prostate volume, residual urine volume, self-ratings for International Index of Erectile Function 5 (IIEF-5), International Prostate Symptom Score (IPSS), Self-Rating Depression Scale (SDS), Aging Male Symptom (AMS) and the Medical Outcomes Study 8-item Short-Form health survey (SF-8).

Results: Following six months of TRT, the levels of testosterone, red blood cells, hemoglobin and hematocrit were significantly increased from baseline, while total cholesterol level was significantly decreased from baseline. Furthermore, TRT led to a significant increase in IIEF-5 score and a significant decrease in IPSS score. Of 30 men who were diagnosed with depression at baseline, only 11 men (36.7%) were still suffering from depression after TRT, and SDS scores were significantly decreased from baseline at month six. Treatment with TRT led to a significant decrease in all scores of the AMS scale as well as a significant improvement in all scores of the SF-8 survey, with the exception of the bodily pain score.

Conclusion: These findings suggest that TRT is an effective and safe treatment for aging Japanese men with LOH. TRT improved depressive symptoms as well as health-related quality of life.     

Prevalence of Sexual Dysfunction and Associated Risk Factors in Middle-Aged and Elderly Korean Men in Primary Care

Although several studies have individually investigated the risk factors for erectile dysfunction (ED), premature ejaculation (PE), and late-onset hypogonadism (LOH), few studies have considered ED, PE, and LOH as categories of sexual dysfunction (SD) within the same population. We therefore aimed to investigate the prevalence of SD and its associated risk factors among men in primary care. Study participants were enrolled by 18 family physicians from 15 hospital-based family practices in Korea between August 2010 and May 2011. Participants answered a questionnaire regarding their demographic characteristics and lifestyle factors as well as the Korean versions of the Androgen Deficiency in the Aging Male, the International Index of Erectile Function, and the Premature Ejaculation Diagnostic Tool questionnaires. SD prevalence was 64.9% among study participants who were ≥ 40 years of age. ED prevalence was 43.7%, PE prevalence was 38.6%, and LOH prevalence was 16.8%. SD prevalence was significantly associated with increased age, overweight, hypertension, diabetes, and depression. These findings highlight the importance of screening questions for SD in primary care, especially among older male patients with the identified risk factors.     

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.     

The effects of testosterone deficiency on male sexual function

Introduction. Patients with late onset hypogonadism (LOH) also suffered from lower urinary tract symptoms (LUTS) and LOH symptoms. The objects of this study are to evaluate the efficacy of testosterone replace therapy (TRT) by testosterone ointment (Glowmin: GL) for LUTS in LOH patients.

Methods. The Aging Male Symptom (AMS) scale, Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF-36), International Index of Erectile Function (IIEF-5) and the International Prostate Symptom Score (IPSS) were obtained from patients with LOH. A total of 41 patients with LOH have been treated with TRT using 6 mg/day of GL for 3 months. Serum free testosterone levels (FT) and these four scores were compared before and after TRT.

Results. Serum FT levels and the scores for the four parameters of AMS, six of eight domains in SF-36, IIEF-5 and total IPSS improved significantly after 3 months TRT. In addition, all IPSS domains also improved significantly, and voiding disturbance seems to have improved more than storage disturbance (P?=?0.0280 vs. 0.0483).

Conclusion. TRT by administration of GL is considered to be effective in the improvement of not only ED and LOH symptoms, but also LUTS (especially voiding disturbance) of patients with LOH.     

The correlation between highly sensitive C-reactive protein levels and erectile function among men with late-onset hypogonadism

We investigated the correlation between highly sensitive C-reactive protein (hs-CRP) levels and erectile function, and assessed the clinical role of hs-CRP levels in men with late-onset hypogonadism (LOH) syndrome. For 77 participants, we assessed Sexual Health Inventory for men (SHIM) score, Aging Male Symptoms (AMS) score and International Prostate Symptom Score (IPSS). We also evaluated free testosterone (FT), hs-CRP, total cholesterol, triglyceride levels, high density lipoprotein cholesterol, hemoglobin A1c, body mass index, waist size and blood pressure. We attempted to identify parameters correlated with SHIM score and to determine the factors affecting cardiovascular risk based on hs-CRP levels. A Spearman rank correlation test revealed that age, AMS score, IPSS and hs-CRP levels were significantly correlated with SHIM score. Age-adjusted analysis revealed that hs-CRP and IPSS were the independent factors affecting SHIM score (r=??0.304 and ?0.322, respectively). Seventeen patients belonged to the moderate to high risk group for cardiovascular disease, whereas the remaining 60 belonged to the low risk group. Age, FT value and SHIM score showed significant differences between the two groups. A multivariate regression analysis demonstrated that SHIM score was an independent factor affecting cardiovascular risk (OR: 0.796; 95%CI: 0.637–0.995).     

The effect of testosterone therapy on lower urinary tract symptoms/bladder and sexual functions in men with symptomatic late-onset hypogonadism

Objective.?To prospectively investigate the effect of testosterone therapy on lower urinary tract symptoms (LUTS)/bladder and sexual functions in men with symptomatic late-onset hypogonadism (SLOH).

Methods.?The study included 25 men (age range 38 to 73 years) presented with sexual dysfunction, having SLOH, at a single university hospital. All men received testosterone replacement therapy with transdermal testosterone 50–100 mg gel per day for one year. Urodynamic studies with pressure-flow analysis, measurement of prostate volume, prostate specific antigen (PSA) and free PSA level, International Prostate Symptom Score (IPSS), Aging Male Symptom (AMS) scale and International Index of Erectile Function (IIEF-5) score were recorded in all men before and after one year of the treatment.

Results.?The mean AMS score significantly decreased from 40.4 ± 7.3 to 28.8 ± 5.31 (p = 0.001), and mean IIEF-5 score significantly increased from 8.84 ± 3.76 to 14.36 ± 3.62 (p = 0.001). The mean maximal bladder capacity and compliance significantly increased (p = 0.007 and p = 0.032, respectively), and mean detrusor pressure at Qmax significantly decreased from pre-treatment to post-treatment (p = 0.017).

Conclusion.?This study suggests that in addition to improvement in sexual functions, testosterone therapy may also improve LUTS/bladder functions by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow in men with SLOH.     

Change in testosterone concentrations over time is a better predictor than the actual concentrations for symptoms of late onset hypogonadism

Abstract

Background. Symptoms of late-onset hypogonadism (LOH) and concentrations of testosterone (T) and bioavailable testosterone (BT) were studied in relation to the data from the same men 5 years earlier.

Methods.?In 2008, 282 men, aged 60–82 years, answered a questionnaire regarding demographic data, medical history, different symptoms of LOH and the 10 questions from the ‘Androgen Decline in Aging Males (ADAM)-questionnaire’. Blood samples were analysed for concentrations of T and calculations were made for BT.

Results.?A total of 87.2% of the questionnaires were returned and analysed, and 75.2% of the responders gave blood samples. The oldest third of the men were most affected by LOH symptoms (p?<?0.05). Both T and BT concentrations decreased during the 5 years (p?<?0.05) but only the symptom ‘less strong erections’ changed significantly (p?<?0.05). Men reporting one of the four specific symptoms from the ‘ADAM-questionnaire’ for the first time in 2008 had a higher loss of T and BT than men who had unchanged or fewer symptoms than that reported in 2003.

Conclusions.?The magnitude of the decrease in concentrations is a better predictor of LOH than are the actual concentrations of T and BT. A combination of symptoms predicts LOH better than any single symptom.     

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study

We evaluated the effects of long-term testosterone replacement therapy (TRT) on the bone mineral density (BMD) in obese patients with metabolic syndrome (MS) and late-onset hypogonadism (LOH). Sixty men (mean age 57 ± 10) with low serum testosterone (T < 320 ng/dL) and MS regardless the presence of osteoporosis were enrolled. Forty men received intramuscular T-undecanoate (TU) four times/year for 36 months and 20 age-matched hypogonadal men with MS in whom T treatment was contraindicated were used as controls. Hormonal, biochemical markers, vertebral and femoral BMD by dual-energy x-ray absorptiometry were measured. At baseline, overall patients had mild osteopenia (lumbar BMD= 0.891 ± 0.097 g/cm(2); femoral BMD= 0.847 ± 0.117 g/cm(2)). TU induced a significant improvement of bone mass after 36 months (lumbar BMD=1.053 ± 0.145 g/cm(2); p < 0.002; femoral BMD=0.989 ± 0.109; p < 0.003 g/cm(2)) with a 5%/year increase and a significant reduction in hs-CRP without changes in body mass index. A direct relationship between serum T and BMD increments at the lumbar (r(2)?= 0.66, p < 0.0001) and femoral (r(2)?=0.52, p < 0.0001) sites was demonstrated. Study adherence was 50% without serious side effects. Long-term TRT in middle-aged men with LOH and MS determines a significant increase in both vertebral and femoral BMD related to increased serum T levels, probably independently from estradiol modifications.     

Change in cytokine levels after administration of saikokaryuukotsuboreito or testosterone in patients with symptoms of late-onset hypogonadism

The purpose of this study was to evaluate plasma cytokine levels after treatment with saikokaryukotsuboreito (SKRBT), which is a herbal medicine, or androgen replacement treatment (ART), for patients with late-onset hypogonadism (LOH)-related symptoms. Thirty-one patients over 40 years of age with LOH-related symptoms were included in this study. SKRBT was given orally three times daily to a total of 7.5 g/day for 15 eugonadal patients and ART was give to 16 hypogonadal patients by intramuscular injection of testosterone enanthate at 125?mg each time every 2 weeks. Plasma levels of testosterone and 18 cytokines, as well as LOH-related symptoms scored according to the Aging Males' Symptoms (AMS) scale, were compared before and more than 2 months after treatment. In the ART group, the total AMS score was decreased and testosterone was increased significantly after treatment. No cytokine variables were altered significantly after the treatment. In the SKRBT group, although the total AMS score was significantly decreased, testosterone did not change. From the evaluation of cytokines, a significant increase was found in interleukin (IL)- 8, IL-13, interferon-γ and tumour necrosis factor-α. We conclude that SKRBT might improve LOH-related symptoms in eugonadal patients through the beneficial effect of cytokines, a mechanism that is quite different from ART.     

Hormone profiles,body mass index and aging male symptoms: results of the Androx Vienna Municipality study

Aging in the male is accompanied by steroid hormonal decline, and men may develop symptoms associated with hypogonadism. Increased awareness of ‘andropause’ in recent years has led to greater demand for hormonal assessments, resulting in a rising burden for health economics. We conducted a cross-sectional study to define men at risk for hypogonadism, in whom further hormonal investigation should be performed.

We examined 664 blue-collar workers aged 40–60 years at their workplace and determined hormonal status and body mass index (BMI). Men with an abnormal urogenital status and those on medication that might affect endocrine status were excluded from the study. All participants completed the validated Aging Male Symptom (AMS) questionnaire and obtained scores for psychological symptoms, somatovegetative symptoms, and sexual symptoms.

Multiple logistic regression analyses revealed a significantly increased risk (represented by the odds ratio) of psychological symptoms for men with low levels of testosterone and/or bioavailable testosterone (BAT). Increased BMI as well as low testosterone levels and/or low BAT levels raised the risk of somatovegetative symptoms. Each decrease of BAT by 1?ng/ml caused an approximately 1.8-fold increase of the risk (odds ratio?=?1.832, p?=?0.005). Additional independent risk factors were increased age and low luteinizing hormone (LH) level. Men aged 55 years with BMI >?28?kg/m² and with somatovegetative symptoms and moderate or severe psychological symptoms had a 7.2-fold increase in the risk of a BAT level <?1.5?ng/ml compared to men without these risk factors (p <?0.001). Sensitivity and specificity were 75% and 71%, respectively.

The AMS score combined with age and BMI provides an easy and convenient method to identify men with probable androgen deficiency who require hormonal assessment.     

Performance of Massachusetts Male Aging Study (MMAS) and androgen deficiency in the aging male (ADAM) questionnaires in the prediction of free testosterone in patients aged 40 years or older treated in outpatient regimen

Abstract

Objective: At present, calculated free testosterone assessment is considered as the gold standard in diagnosing male hypogonadism. However, this assessment is not available for all the individuals diagnosed with decreased testicular function. The investigators of this study were, thus, prompted to evaluate whether the androgen deficiency in the aging male (ADAM) and the Massachusetts Male Ageing Study (MMAS) questionnaires could be used to replace biochemical parameters in the diagnosis for hypogonadism in men aged 40 years and above.

Methods: We evaluated 460 men, aged 40 years and above, all volunteers of a screening program for prostate cancer based at the Hospital de Clínicas of Porto Alegre. In this study, we assessed the efficiency of the ADAM and MMAS questionnaires in diagnosing Brazilian men with low levels of total, calculated free and bioavailable testosterone.

Results: The sensitivity of the ADAM questionnaire in diagnosing the calculated free testosterone was 73.6%, whereas specificity was 31.9%. ADAM could be used to properly classify our cohort into normal or hypogonadal individuals in 52.75% of the cases. The sensitivity of the MMAS questionnaire was 59.9%, whereas the specificity was 42.9%, resulting in a successful classification of 51.4% of the patients.

Conclusion: The ADAM and MMAS questionnaires showed adequate sensitivity in diagnosing male patients with low levels of free testosterone. However, because of the lack of specificity, these tools cannot replace calculated free testosterone assessments in men aged 40 years and above.     

Testosterone,testosterone therapy and prostate cancer

Abstract

With prostate cancer not observed in eunuchs and total androgen suppression by castration an effective first-line treatment for advanced prostate cancer, the dramatic regression seen in tumour symptoms after castration, lead to the theory that high levels of circulating androgens were a risk factor for prostate cancer. This theory however, ignored the effects testosterone variations within a physiologic range could have on early tumour events and since the early 2000s, clinical evidence discounting testosterone as a linear mechanistic cause of prostate cancer growth mounted, with alternative mechanistic hypotheses such as the saturation model being proposed. Together with a growing understanding of the negative health effects and decreased quality of life in men with testosterone deficiency or hypogonadism, a paradigm shift away from testosterone as a prostate cancer inducer occurred allowing clinicians to use testosterone therapy as potential treatment for men with difficult and symptomatic hypogonadism that had been previously treated for prostate cancer. In this review we contextualise the idea of testosterone as a risk factor for prostate cancer inducement and compile the most current literature with regards to the influence of testosterone and testosterone therapy in prostate cancer.     

Testosterone supplementation: what and how to give

Several epidemiological studies have demonstrated a gradual decrease of serum testosterone with aging in men. A considerable number of men will experience hypogonadal androgen levels, defined by the normal range for young men. Thus, in addition to the long-standing use of androgen replacement therapy in the classical forms of primary and secondary hypogonadism, age-associated testosterone deficiency has led to considerable developments in application modes for testosterone. Since oral preparations of testosterone are ineffective, due to the first-pass effect of the liver, or, in case of 17 α-alkylation, cause hepatotoxicity, intramuscular injection of long-acting esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. However, the large fluctuations of serum testosterone levels cause unsatisfactory shifts of mood and sexual function in some men; combined with the frequent injections, this delivery mode is thus far from being ideal. In contrast, the transdermal testosterone patches are characterized by favorable pharmacokinetic behavior and have proven to be an effective mode of delivery. Safety data over 10 years indicate no negative effect on the prostate. Nevertheless, the scrotal testosterone patch system is hampered by the application site, which is not easily accepted by many subjects; the non-scrotal patch has a high rate of skin irritations. In view of the drawbacks of the currently available preparations, the most recent developments in testosterone supplementation appear to be highly promising agents. Androgen, which has been available in the United States since mid-2000, will be introduced this year in most European markets as Testogel ® , a hydroalcoholic gel containing 1% testosterone. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and to correct the signs and symptoms of hypogonadism. The gel has shown to be very effective and successful in American patients, who have benefited from its availability for almost 3 years. Furthermore, in phase II and III clinical studies, the intramuscular injection of 1000 mg testosterone undecanoate every 12-15 weeks has led to extremely stable serum testosterone levels for a prolonged period of time and has resulted in excellent efficacy. It is very likely in the future that these products will be the mainstay of testosterone supplementation. Whereas the indication for testosterone substitution for men with classical forms of hypogonadism is unequivocal, the use of testosterone in men with ageassociated hypogonadism is less uniformly accepted. Yet, the few studies addressing this question indicate that men with testosterone serum levels below the lower normal limit for young adult men and with lack of energy, libido, depressed mood and osteoporosis may benefit from testosterone supplementation. However, it should be kept in mind that the experience documented in studies is limited. Nevertheless, serious side-effects, especially in regard to the prostate, did not occur, with the longest study extending over 3 years.     

Testofen,a specialised Trigonella foenum-graecum seed extract reduces age-related symptoms of androgen decrease,increases testosterone levels and improves sexual function in healthy aging males in a double-blind randomised clinical study

This study examined the effect of Testofen, a specialised Trigonella foenum-graecum seed extract on the symptoms of possible androgen deficiency, sexual function and serum androgen concentrations in healthy aging males. This was a double-blind, randomised, placebo-controlled trial involving 120 healthy men aged between 43 and 70 years of age. The active treatment was standardised Trigonella foenum-graecum seed extract at a dose of 600?mg/day for 12 weeks. The primary outcome measure was the change in the Aging Male Symptom questionnaire (AMS), a measure of possible androgen deficiency symptoms; secondary outcome measures were sexual function and serum testosterone. There was a significant decrease in AMS score over time and between the active and placebo groups. Sexual function improved, including number of morning erections and frequency of sexual activity. Both total serum testosterone and free testosterone increased compared to placebo after 12 weeks of active treatment. Trigonella foenum-graecum seed extract is a safe and effective treatment for reducing symptoms of possible androgen deficiency, improves sexual function and increases serum testosterone in healthy middle-aged and older men.     

Effects of testosterone replacement therapy on nocturia and quality of life in men with hypogonadism: a subanalysis of a previous prospective randomized controlled study in Japan

Abstract

Objective: We investigated the effects of testosterone replacement therapy (TRT) on nocturia and general health among men with hypogonadism and nocturia.

Methods: From our previous EARTH study population, 64 patients with a clinical diagnosis of nocturia (two or more times per one night) and hypogonadism, comprising the TRT group (n?=?31) and controls (n?=?33), were included in this analysis. The TRT group was administered 250?mg of testosterone enanthate as an intramuscular injection every 4 weeks for 6 months. All patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score and Short Form-36 health survey at baseline and 6-month visit. These categories were compared based on changes from baseline to the 6-month visit between TRT and control groups.

Results: At the 6-month visit, the TRT group had a significant decrease in IPSS question no. 7 and AMS question no. 4, whereas no significant changes were observed in the control group. Additionally, role limitation because of health program, vitality and mental health domains were significantly improved in the TRT group.

Conclusions: Six-month TRT may improve nocturia, sleep conditions and quality of life among men with hypogonadism and nocturia.     

RigiScan data under long-term testosterone therapy: improving long-term blood circulation of penile arteries,penile length and girth,erectile function,and nocturnal penile tumescence and duration

Background: Late-onset hypogonadism (LOH) presents with low serum testosterone (TT) levels and sexual and nonsexual symptoms. Erectile dysfunction affects a man’s self-esteem and as a result partner relationship and quality of life.

Objectives: To investigate the andrological clinical profile outcomes of testosterone therapy (TTh) in men (n?=?88) with symptomatic LOH complaints and symptoms.

Main outcome measures: Erectile function was assessed using the International Index of Erectile Function-5 questionnaire at baseline and at 6 and 12 months of TTh. In addition, penile length was measured at baseline and 12 months. We also evaluated nocturnal penile tumescence (NPT, using RigiScan) and blood flow of cavernous arteries (penile Doppler ultrasonography) at baseline and 12 months of TT.

Materials and methods: Eighty-eight LOH men (M_age 51.1 years) with erectile dysfunction, all with serum TT?<10.4?nmol/L before TTh. Patients received intramuscular long-acting testosterone undecanoate for 12 months.

Results: Following TTh, in all patients, serum TT levels were restored within 3 months to normal levels. Compared with baseline values, erectile function significantly improved at 6 (mean score increase 1.95) and 12 months (mean score increase 2.16). No significant changes in penile length were observed. NPT significantly improved at 12 months in terms of both the frequency (mean increase 1.27 times) and duration of rigidity (mean increase 5.12?min). As regards the blood flow of the cavernous arteries, we observed a significant improvement (decrease of 1.16?cm/s) and end diastolic velocity of the penile arteries.

Conclusion: TTh in men with LOH resulted in improvement of the erectile function, NPT, and to some extent the blood flow of the cavernous arteries.     

The efficacy and safety of short-acting testosterone ointment (Glowmin) for late-onset hypogonadism in accordance with testosterone circadian rhythm

Introduction: It is well known that there is a reduction of circadian rhythm in blood testosterone levels with aging. Our previous report revealed that 3?mg of short-acting testosterone ointment (Glowmin: GL) elevated serum testosterone levels to within the physiological range for 4–6?h. The aim of this study was to clarify the clinical efficacy and safety of GL used topically once every morning, to enhance the circadian rhythm of testosterone, for late-onset hypogonadism (LOH).

Methods: A total of 61 LOH patients received 3?mg of GL topically once a day in the morning on scrotal skin for 24 weeks. The clinical efficacy of GL was evaluated by the aging males symptoms (AMS) scale, and blood sampling tests were measured before and after GL treatment.

Results: Mean patients age was 55.3?±?9.2 years old. Total AMS scores at 4, 12, and 24 weeks after GL treatments significantly decreased. The results of sub-analysis of AMS, including psychological, physical, and sexual factors also significantly improved after GL treatments. No severe adverse reactions or abnormal laboratory data were reported.

Conclusions: This study shows that TRT for LOH with once daily GL treatment supports testosterone circadian rhythm and should be considered to be an effective and safe therapy for LOH.