Clinical Practice Manual for Late‐onset Hypogonadism Syndrome

With the aging of the population, the quality of life (QOL) of middle-aged and elderly men has come into question and it has been taken up from an interdisciplinary standpoint in recent years. Partial androgen deficiency of the aging male (PADAM) or late-onset hypogonadism (LOH) is a syndrome consisting of symptoms caused by partial deficiency of androgens, but the time of onset varies and the epidemiological status is unclear. Therefore, in Japan to date, this syndrome has been considered as a general phenomenon associated with aging, the medical authorities have not reacted and patients are not being treated. In Western countries however, this phenomenon has attracted attention in relation to geriatrics and reproductive endocrinology since the 1980s. In 1998, the International Society for the Study of the Aging Male (ISSAM) was founded to conduct basic and clinical research, to provide postgraduate education and to engage in publicity activities for the enlightenment of the public. The social background is characterized by the appearance of a very rapidly aging society with longer average life spans. The importance of improving the health of the elderly and preventive medicine as government policy has increased. Improving the health of the elderly not only promotes self-reliance of the elderly but also increases the work force. A high QOL is also possible. The main topic for healthcare in the 21st century is how to maintain the QOL of the elderly. In women, hormone replacement therapy (HRT) is widely applied internationally, but specific healthcare for elderly men appears to be limited to the widespread use of phosphodiesterase type 5 (PDE5) inhibitors to treat erectile dysfunction (ED). Although the delay in healthcare policies for elderly men is not a direct reason, a large gap has appeared between the average life spans of men and women in recent years and in Japan, men have a shorter life span than women by about seven years. In response to this sense of crisis, the World Health Organization (WHO) issued the Geneva Manifesto in 1997 and 'healthy aging for men' became an international movement. ISSAM was established in 1998 with the goal of 'aging male research on gender specific issues in male health'. The first meeting of the society in Asia was held in Malaysia in 2001 and this topic was adopted on an international level from an early stage. The reason appeared to be strong economic and social concern that Asian countries with a current pyramid-type population distribution will become aging societies with a lower birth rate than in developing countries. Japan has already become an aging society with a low birth rate. In the national census (summary) in 2005, the elderly population of 65 years and older accounted for about 21% of the total population, the highest in the developed world. In Japan, scientific research on the aging male started at about the same time as in the rest of Asia, and the Japanese Society for the Study of the Aging Male (JSSAM) was founded in November 2001 with Yoshiaki Kumamoto, professor emeritus of Sapporo Medical University, and Hajime Nawata, professor of Kyushu University as representative facilitators. The goal of this society is 'undertaking basic, clinical and social research and surveys on policies for the diagnosis, treatment and prevention of male-specific medical problems, and contributing widely to men's health by development, promotion and spread of proper healthcare'. As mentioned above, the concept of research on the aging male is being promoted as 'healthy aging for men' but almost no actual treatment for such patients has been performed. When the JSSAM was established, so-called 'male climacteric symptoms' or 'male menopause' was popular in the media, and when such treatment was started, many patients mainly with a chief complaint of climacteric symptoms appeared in medical practice. These patients included many with psychiatric problems such as depression and considerable confusion arose in clinics and hospitals. Based on this background, the Subcommittee on Endocrinology, Reproductive Function and Sexual Function of the Japanese Urological Association asked the Scientific Committee to prepare a clinical practice guideline, and a working group was organized to prepare the guideline by a collaborative team from the Japanese Urological Association and JSSAM after a review by the Board of Directors. In this clinical practice manual, the term 'late–onset hypogonadism (abbreviation: LOH)' syndrome was adopted as the term that best expresses this condition medically. In order to recommend standard procedures for diagnosis, treatment, prevention and monitoring of adverse reactions due to androgen replacement therapy (ART) and post-treatment assessments, a literature survey of clinical papers was performed, but since treatment of LOH Syndrome has just started, almost all papers had a low recommendation rank. Therefore, the name was changed to 'Clinical Practice Manual for Treatment of Late-onset Hypogonadism (LOH) Syndrome' ('Manual' hereinafter) instead of the initially planned 'clinical practice guideline'. Care of LOH Syndrome is in its initial stages and such treatment requires careful consideration. Since many men visiting medical institutions at present complain of 'climacteric symptoms', measures must be taken to have this disease recognized in the mental health field. In the future, it will be necessary to establish evidence for treatment of LOH Syndrome from the broad perspective of promotion of 'healthy aging for men.' This 'Manual' is the first edition aimed at gathering evidence through future diagnosis and treatment of LOH and it is hoped that it will serve as a reference for routine medical practice. The term 'andropause' was used in the past for hypogonadism of the aging male, but internationally, the expressions androgen decline in the aging male (ADAM) or partial androgen deficiency of the aging male (PADAM) have been widely used to express a 'set of symptoms associated with androgen deficiencies due to aging.' In Japan, the PADAM concept has also become established.1–3 However, the pathophysiology of men with the so-called 'climacteric symptoms' visiting medical institutions is complex. Patients in the stage of early male climacteric show a high percentage of stress-related psychosomatic symptoms and in many cases, androgen deficiency symptoms come to the fore in the mature stage after late male climacteric. Male climacteric shows a complex pathophysiology and it cannot be explained simply as a deficiency in androgens associated with aging in all cases. Since PADAM and male climacteric were considered to have the same meaning, it cannot be denied that this has resulted in confusion in medical practice. In a joint recommendation by the International Society of Andrology (ISA), ISSAM and the European Association of Urology (EAU) in 2005, use of the term 'LOH' was recommended,4–6 which was defined as 'A clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels. It may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems'.7 The key words in this definition are deficiency in androgen levels, aging, detriment in the quality of life and multiple organ dysfunction. The basic concept of 'healthy aging for men' is the prevention of reduction in organ functions caused by a deficiency in androgen levels associated with advancing age by androgen replacement. In this Manual, the LOH Syndrome is used to accurately express this pathophysiology medically in keeping with this concept. Table 1-1 shows the signs and symptoms included in this syndrome based on the above recommendation. LOH Syndrome starts with the evaluation of gonadal functions. Hormone testing is centered on testosterone blood levels and it is necessary to analyze test values based on an adequate understanding of biochemical diversity and characteristics. General laboratory tests and urological tests are useful in deciding the indications of ART as well as in the screening of the underlying diseases, and in simplifying the differential diagnosis of LOH Syndrome. LOH patients are often examined for unidentified complaints and questionnaires are essential in the differentiation from mental diseases, especially depression. Since relatively young men are also examined for this disorder, diagnosis without any predictions based on age is necessary. Sex hormones are controlled by precedence from the hypothalamus and pituitary gland and they can undergo changes caused by organic diseases such as tumors or inflammatory disease, aging or extrinsic factors such as drugs. The measurement of gonadotropin is useful in the differentiation between primary and secondary hypogonadism. Therefore, in diagnosis for LOH, it is necessary to measure pituitary hormones, the luteinizing hormone (LH) and the follicle-stimulating hormone (FSH). Prolactin (PRL) causes hypogonadism and it is recommended to measure PRL since hyperprolactinemia is caused by prolactin-producing tumors and by the adverse reactions of drugs such as sulpiride. Deficiencies in growth hormone (GH)/insulin-like growth factor (IGF-1) can explain reduced muscle strength, increased visceral fat and reduced bone density and their measurement is also useful. The main androgen is the testosterone produced in the testes. However, the active testosterone in the blood is free testosterone, which makes up only 1–2% of total testosterone. Total testosterone consists of three fractions: the sex hormone binding globulin (SHBG)-bound testosterone, albumin-bound testosterone and free testosterone. Since albumin-bound testosterone can be easily separated from albumin, it is called bioavailable testosterone (BAT), which is biologically active, when combined with free testosterone (Fig. 1). SHBG however, is tightly bound to testosterone and this combination is biologically inactive. Since SHBG bound testosterone gradually increases with age, BAT is considered to show a relative decrease with no change in total testosterone. If total testosterone, SHBG and albumin are measured, it is possible to obtain calculated free testosterone and calculated BAT by such calculations (http://www.issam.ch/freetesto.htm). Forms of testosterone. Vermeulen A. Diagnosis of partial androgen deficiency in the aging male. Ann. Endocrinol. 2003; 64: 109–114. Because the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) gradually decrease with aging, they can serve as a senility indicator and might cause LOH signs and symptoms. Blood levels of cortisol basically show no changes throughout life, but they are known to be altered by stress, which makes these values useful in the differentiation of LOH and transient stress. In the guidelines of the Consensus Committee of the Endocrine Society in the United States (2001),9 the standard value for indication of ART is total testosterone of less than 2.0 ng/mL. For patients with values of 2.0–4.0 ng/mL, free testosterone and BAT are recommended as references. In the ISA, ISSAM and EAU recommendation of Lunenfeld et al. LOH standard value is a total testosterone of less than 8 nmol/L (2.31 ng/mL) and the normal value is not less than 12 nmol/L (3.46 ng/mL). Therefore, patients with values of greater than 8 and less than 12 nmol/L (2.31–3.46 ng/mL) are defined as borderline. In such patients, determination of calculated free testosterone is recommended and a diagnosis and treatment algorithm should be prepared.7 According to the detailed policies of Nieschlag et al.,10 total testosterone and SHBG are measured by a chemistry test using blood collected between 7 and 11 am. Thus, the algorithm for diagnosis of LOH Syndrome overseas is based on total testosterone, not free testosterone. From studies on healthy men in Japan however,11 it was found that decreases in total testosterone with age are very slight, but free testosterone values decrease significantly with aging (Fig. 2). Total testosterone and free testosterone cannot be measured simultaneously for LOH Syndrome because of health insurance coverage. Therefore, the Working Committee on Clinical Practice Guidelines for Late-onset Hypogonadism recommends that free testosterone should be the diagnostic test for LOH Syndrome. Distribution of free testosterone with age. Free testosterone cannot be expressed uniformly as a mean value for the reason described previously. Therefore, the data in Figure 2 was used as the standard diagnostic criteria for LOH Syndrome and the normal lower limit was set at a mean−2SD value of 8.5 pg/mL for men in their twenties. Patients with values of greater than 8.5 pg/mL and less than 11.8 pg/mL, 70% of the mean value for men in their twenties (young adult mean: YAM) are recommended to be given ART as cases with a tendency toward low androgen levels (LOH borderline cases). The reason for applying the concept of the YAM percentage of the free testosterone value is that the mean values by age range only decrease to 80% from andropause through the mature stage, when LOH Syndrome occurs most frequently, using the YAM value of total testosterone. However, the YAM value of free testosterone shows a linear decrease with aging and drops to 50%, indicating that the effect of the decrease in the standard level with aging is more marked for free testosterone than for total testosterone. Even within the standard ranges (mean−2SD) of total testosterone and free testosterone, it is possible to detect an abnormal value with assessment using the YAM percentage. The YAM value is already applied in routine clinical practice for the evaluation of bone mineral density in osteoporosis based on evidence based medicine (EBM).12 The algorithm for diagnosis of LOH in Japan (Fig. 3) has been prepared for reference. Differences in the standard value of free testosterone in this Manual and the standard calculated free testosterone value for LOH recommended by ISA, ISSAM and EAU7 are due to differences in the measurement and calculation methods and caution is required when making comparisons.13 Algorithm of diagnosis of Late-onset Hypogonadism (LOH). There are currently no specific physical findings or test parameters for LOH Syndrome. At present, it is valid to use general parameters for excluding other serious diseases and prostate diseases and for assessment before treatment and during the course of treatment associated with ART. Table 1-2 shows the required minimum parameters for assessment as the essential parameters that can be measured routinely, and the optional values. Androgens are known to act on erythrocyte production, glucose metabolism and lipids. In recent years, the metabolic syndrome based on visceral fat obesity has attracted attention and in consideration of the antiobesity effects of testosterone, LOH Syndrome might be complicated with the metabolic syndrome. Evaluation of the metabolic syndrome is performed using the BMI (height and weight) and the waist-hip ratio. Diagnostic criteria were published in April 2005 based on a consensus of eight societies including the Japanese Society of Internal Medicine.14 A waist circumference of Japanese males of 85 cm or more, equivalent to a visceral fat area of 100 cm2 or more on CT, was applied as the essential item in these diagnostic criteria. A visual examination including the pudendal region is very important as an indicator of androgen deficiency of LOH. Palpation of the testes and measurement of testicular volume In palpation of the testes, epididymis, ductus deferens and spermatic cord are palpated in that order. The size and hardness or softness of the testes is especially important. Testicular volume is measured by a testicular ultrasound examination or a testicular volume meter. Observation of body hair It is important to observe changes in facial and pubic hair since they are often correlated with androgen concentration. Evaluation of sexual function Sexual function is usually assessed by the International Index of Erectile Function (IIEF) or the simplified IIEF5. 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The of Index of is useful for levels in the elderly in the The Index consists of three self-reliance and social There are a total of and This is considered useful in assessment of symptoms of LOH. Androgens have many important activities in men and they have on the prostate bone and sexual to sexual function of sexual and erectile A relation with of and is but the actual relation unclear. on the muscle and increased muscle and muscle on the bone promotion of and of bone of the bone of testosterone occurs the of in the have given an in bone mineral density as an effect of ART on The on erythrocyte a effect on erythrocyte In clinical it was that increased during above the normal value of However, no significant in was found when testosterone was The effects on and body fat a decrease in body fat due to Total and to In research on disease using testosterone, it was that depression due to was by ART in patients with In research, at the time of was and had no effect on the of It was also that the of be and the level of increased. However, it is not ART is with the prevention of the onset of ART is for men the age of with signs and symptoms of LOH when is a in the free testosterone blood ART is treatment when the free testosterone blood level is less than the 8.5 pg/mL, the mean−2SD of men in their ART should be considered for men with a free testosterone level of less than 11.8 pg/mL, 70% of the mean value of men in their twenties greater than 8.5 and less than 11.8 pg/mL, which to be but is within the normal Based on the of signs and ART is a treatment after the and of ART have been explained to the ART is not performed when the free testosterone blood level is 11.8 pg/mL or and the treatment is considered based on the symptoms. When sexual function symptoms are a is When symptoms are a or psychosomatic is and or are When physical symptoms are osteoporosis is are held with a and therapy is and for in muscle strength, is given on ART is not performed in patients with the diseases or in Table The three ART are is at time or three or time three to Since the testosterone blood levels are in about to seven after caution is required because of the that the serum testosterone levels will normal values and a level when the is It is recommended that blood be collected about to seven after and the of free testosterone in the blood be gonadotropin is at time or a or The test is performed on patients with normal blood levels and the response of testosterone in the blood is is The is that changes in blood testosterone are relatively when with of testosterone and the is that many are is applied at a of time or a on the of the to of testosterone is and testosterone in the blood are With all evaluation is performed three after the of If effects are treatment is with caution adverse for male testosterone are and other Since the of is by caution is required including the of the Androgens are hormones that act on many and that should be considered when ART diseases, metabolism prostate testicular and changes in or diseases It has been that the of disease is high in patients with However, no effects of ART on the have been and testing is required on clinical symptoms. metabolism adverse effects on metabolism have been found with ART when blood testosterone levels not the range during in blood levels of have been at high that requires of or of ART is in of patients with hypogonadism with treatment, it is necessary to by blood The criteria for are blood or more, of or more and of In such of ART and by a are dysfunction has been found in about of patients testosterone but dysfunction due to of testosterone or of testosterone is Since ART can ART is for patients with adverse reactions increased body hair and have been but they are not significant adverse At physical examination and laboratory an evaluation of using and of should be In and are especially important. In blood and must be including must be Blood tests should be to three and after the of the treatment and a Treatment must be or the is as required based on the test values. and should be and are treatment is or should be and to as are not but when are by tests performed, ART should be and an evaluation by a is is required in relation to prostate disease, which is a for ART. ART is in cases of prostate and relatively for ART and prostate disease are from three prostate and the serum prostate specific In with a the ART group no of symptoms or due to In ART of in elderly no changes in prostate rate or were However, the prostate is known to be androgen and prostate usually decreases with It is necessary to of the prostate due to ART. There is evidence that ART causes prostate but are the from to clinical In prostate appeared in of patients given ART for but this was the same as the general However, the effects of treatment for more than are unclear. Therefore, the serum value must be as described monitoring is important for early of prostate The criteria for ART are in Figure Evaluation of values at of and during ART. of less than 2.0 is recommended as the standard value for indicating ART. There is no evidence for this standard that a standard value of is that ART is not performed at ng/mL. In are that and are to in the low testosterone In this Manual, the standard value was set at a low ART should be considered after a careful when is greater than 2.0 and less than ng/mL. In Western ART is performed after prostate When is greater than or when other findings of prostate are a should be ART should be and a when increases by greater than at or greater than at after of ART. Treatment of LOH is usually for a When ART is performed, blood levels of testosterone basically in all It is necessary to the signs and symptoms of LOH associated with in blood testosterone levels as treatment Since evidence has not been established for the therapeutic effects on LOH Syndrome in it is necessary to evidence by This is the of this The therapeutic effects are usually at three at after the of treatment and the of the including or treatment, is When treatment is performed for more than it is important to observe in the symptoms In the recommendation by ISSAM in it of the course during ART is the of the and the The of of patients by must be and the patients must to these Thus, the importance of by and patients is This recommendation the that replacement therapy is performed for life and of the course is also a However, time is required before this is in At present, it cannot be that it is necessary to for the rest of the life ART is started, and it is necessary for the and to have a understanding of the treatment When adverse reactions are cases when treatment should be the treatment was found to be