SEARCH

SEARCH BY CITATION

Introduction

  1. Top of page
  2. Introduction
  3. [1] Definition of LOH
  4. [2] Diagnosis
  5. [3] Treatment
  6. [4] Adverse reactions of androgen replacement therapy (ART) and their monitoring
  7. [5] Assessment after treatment
  8. References

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.

[1] Definition of LOH

  1. Top of page
  2. Introduction
  3. [1] Definition of LOH
  4. [2] Diagnosis
  5. [3] Treatment
  6. [4] Adverse reactions of androgen replacement therapy (ART) and their monitoring
  7. [5] Assessment after treatment
  8. References

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.

Table 1-1.  Signs and symptoms of Late-onset Hypogonadism (LOH) Syndrome
  1. Lunenfeld et al. Aging Male 2005; 8: 56–58.

1)The easily recognized features of diminished sexual desire (libido) and erectile quality and frequency, particularly diminished nocturnal erections.
2)Changes in mood with concomitant decreases in intellectual activity, cognitive functions, spatial orientation ability, fatigue, depressed mood and irritability.
3)Sleep disturbances.
4)Decrease in lean body mass with associated diminution in muscle volume and strength.
5)Increase in visceral fat.
6)Decrease in body hair and skin alterations.
7)Decreased bone mineral density resulting in osteopenia, osteoporosis and increased risk of bone fractures.

[2] Diagnosis

  1. Top of page
  2. Introduction
  3. [1] Definition of LOH
  4. [2] Diagnosis
  5. [3] Treatment
  6. [4] Adverse reactions of androgen replacement therapy (ART) and their monitoring
  7. [5] Assessment after treatment
  8. References

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.

1 Hormone testing8

1) Gonadotropin and other pituitary hormones

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.

2) Testosterone

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).

image

Figure 1. Forms of testosterone. Vermeulen A. Diagnosis of partial androgen deficiency in the aging male. Ann. Endocrinol. 2003; 64: 109–114.

Download figure to PowerPoint

3) Adrenal steroids

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.

2 Standard values for ART indications

1) Overseas values

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.

2) Japanese values

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.

image

Figure 2. Distribution of free testosterone with age.

Download figure to PowerPoint

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

image

Figure 3. Algorithm of diagnosis of Late-onset Hypogonadism (LOH).

Download figure to PowerPoint

3 Laboratory tests (Table 1-2)

Table 1-2.  Tests for Late-onset Hypogonadism (LOH)
  1. BMI, body mass index; DEXA, Dual energy X-ray absorptiometry; ECG, electrocardiogram; PSA, prostate specific antigen.

Essential tests 
Physical findingsHeight, weight, BMI, waist circumference (umbilical circumference), blood pressure, grip strength (both hands)
ExaminationsChest X-ray, ECG
HematologyEspecially hemoglobin, hematocrit, RBC count
Blood chemistryEspecially, TC, TG, HDL-C, LDL-C, GOT, GPT, ALP, γ-GTP, Ca, P
UrinalysisProtein, glucose, occult blood
Glucose toleranceFBS, HbA1c
Tumor markerPSA
Optional tests 
Bone mineral densityDual energy X-ray absorptiometry (DEXA)
Body fat ratio 
Urological tests 
Physical testsTesticular palpation, testicular volume measurement, pudendum (penis), body hair (facial hair, pubic hair), digital rectal examination of the prostate
QuestionnairesInternational Index of Erectile Function (IIEF)
International Prostate Symptom Score (IPSS)
1) General laboratory tests

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.

2) Urological tests

A visual examination including the pudendal region is very important as an indicator of androgen deficiency of LOH.

  • 1
    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.

  • 2
    Observation of body hair

It is important to observe changes in facial and pubic hair since they are often correlated with androgen concentration.

  • 3
    Evaluation of sexual function
    • (a) 
      Sexual function is usually assessed by the International Index of Erectile Function (IIEF) or the simplified IIEF5. The results are useful in assessment of therapeutic effects.
    • (b) 
      Nocturnal penile tumescence (NPT) and morning erection are simple and useful assessments of sexual function. The erectometer can also be used as a simplified method.
  • 4
    Prostate evaluation
    • (a) 
      Evaluations of symptoms related to urination and voiding conditions are useful for differentiation from prostate diseases. The International Prostate Symptom Score (IPSS) is a diagnostic aid.
    • (b) 
      A digital rectal examination of the prostate is important for diagnosis of prostatic hyperplasia and prostate cancer.

4 Questionnaires

1) Questionnaires used in LOH Syndrome diagnosis

Various symptoms are caused by reduced testosterone levels in the aging male, and questionnaires are widely used for screening. The most widely used questionnaire at present is the Aging males' symptoms (AMS) scale by Heinemann et al.15,16 (Table 1-3). The self-rating questionnaire consists of five questions on psychological factors (questions 6–8, 11, 13), seven on physical factors (questions 1–5, 9, 10) and five on sexual function factors (questions 12, 14–17) for a total of 17 questions. Each question is answered in five grades: ‘none’, ‘mild’, ‘moderate’, ‘severe’ and ‘extremely severe’ and the grade is assigned one to five points. The AMS score was found to be effective for 116 men over the age of 40 and 992 German men over the age of 40 were tested for verification. It has now been translated into 14 languages and is useful in international comparisons of LOH symptoms.17

Table 1-3.  Aging males' symptoms (AMS) scale by Heinemann et al.
 SymptomsNoneMildModerateSevereExtremely severe
Points12345
  1. Level of severity: 17–26 points, none; 27–36 points, mild; 37–49 points, moderate; more than 50 points, severe.

  2. (Draft Japanese translation: Department of Urology, Sapporo Medical University School of Medicine)

1Decline in your feeling of general well-being (general state of health, subjective feeling)12345
2Joint pain and muscle ache (lower back pain, joint pain, pain in a limb, general back ache)12345
3Excessive sweating (unexpected/sudden episodes of sweating, hot flushes independent of strain)12345
12345
4Sleep problems (difficulty in falling asleep, difficulty in sleeping through, waking up early and feeling tired, poor sleep, sleeplessness)12345
12345
5Increased need for sleep, often feeling tired12345
6Irritability (feeling aggressive, easily upset about little things, moody)12345
7Nervousness (inner tension, restlessness, feeling fidgety)12345
8Anxiety (feeling panicky)12345
9Physical exhaustion/lacking vitality (general decrease in performance, reduced activity, lacking interest in leisure activities, feeling of getting less done, of achieving less, of having to force oneself to undertake activities)12345
10Decrease in muscular strength12345
11Depressive mood (feeling down, sad, on the verge of tears, lack of drive, mood swings, feeling nothing is of any use)12345
12Feeling that you have passed your peak12345
13Feeling burnt out, having hit rock bottom12345
14Decrease in beard growth12345
15Decrease in ability/frequency to perform sexually12345
16Decrease in number of morning erections12345
17Decrease in sexual desire/libido (lacking pleasure in sex, lacking desire for sexual intercourse)12345

When this questionnaire was applied to urology department outpatients (without complaint for andropause), the overall severity was found to increase with aging, but it has often been reported that there is no clear correlation coefficient between the AMS score and blood levels of total testosterone.18 No papers have appeared on the correlation with free testosterone to date and this point awaits further study. Since some questions show different nuances based on German culture such as Question 12 ‘Feeling that you have passed your peak’ classified as a sexual factor, caution is required when using this questionnaire in Japan.

The Male Climacteric Symptom Scale by Kumamoto (MCS-K) (Table 1-4) is a questionnaire on male climacteric symptoms developed in Japan. In males with male climacteric symptoms, the total ‘MCS-K’ score and the AMS score show a significant correlation. However, this form has not been adequately validated for diagnosis and evaluation of LOH Syndrome and future studies are required.

Table 1-4.  Male Climacteric Symptom Scale by Kumamoto (MCS-K)
 SymptomsAlmost noneModerateSevereVery severe
A: Psychological factors1. General physical condition not good, irritable1234
2. Have trouble sleeping (Insomnia)1234
3. Feeling of anxiety, loneliness1234
4. Often uneasy, depressed mood1234
B: Physiological factors5. Hot flushes, light-headedness, excessive sweating1234
6. Palpitations, shortness of breath, suffocating feeling1234
7. Dizziness, nausea1234
8. Tire easily (fatigue)1234
9. Headache, head feels stuffy, neck feels stiff1234
10. Lower back pain, joint pain in limbs1234
11. Stiffness in limbs1234
12. Numbness, tingling sensation, cold feeling in limbs1234
C: Sexual factors13. Decrease in sexual desire1234
14. Decrease in erectile power1234
SymptomsAt least 2 or 3 times a fortnightOnce a weekOccasionallyAlmost never
15. Aware of morning erection1234
SymptomsAt least 2 or 3 times a fortnight1 or 2 times a monthLess than once a monthAlmost never
16. Frequency of sex1234
Questions for reference    
SymptomsAlmost noneModerateSevereVery severe
Urination factorsVoiding difficulties, long time needed for urination1234
Often has to urinate at night1234
Cannot wait for urinary sensation, leakage1234
2) Diagnosis of depression

The mental symptoms of LOH Syndrome are similar to those of depression and differentiation is difficult. As a mental disorder, depression is broadly classified into two types: major depressive disorders and dysthymic disorders. Diagnostic and Statistical Manual of Mental Disorders, the 4th Edition (DSM-IV), the diagnostic criteria of the American Psychiatric Association, is often used for diagnosis of depression, but structured interviews are recommended to increase the reliability of the results. For this reason, the Mini International Neuropsychiatric Interview (M.I.N.I.) is widely used.19,20 The M.I.N.I. was developed for the application of DSM-IV in routine practice and is designed to permit simple application in a short time.

Procedures for structured interviews using M.I.N.I. for major depressive disorders are shown in Table 1-5. With this procedure, the form is read out directly and an explanation is added if the meaning is not clear so that accurate replies can be obtained. First, there are two questions in a colored square. If the answers to both questions are ‘No’, it is judged negative for major depressive disorder and if the answer to either question is ‘Yes’, the diagnosis proceeds to the final stage based on the instructions.

Table 1-5.  Major depressive episode – The Mini-International Neuropsychiatric Interview (M.I.N.I), Japanese version 5.0.0 (2003), Modified
A1Have you been consistently depressed or down, most of the day, nearly every day, for the past two weeks?NoYes
A2In the past two weeks, have you been much less interested in most things or much less able to enjoy the things you used to enjoy most of the time?NoYes
Is A1 or A2 coded Yes?NoYes
A3Over the past two weeks, when you feel depressed or uninterested:  
 aWas your appetite decreased or increased nearly every day? Did your weight decrease or increase without trying intentionally (i.e. by ± 5% of body weight or ±3.5 kg for a 70 kg person in a month)?NoYes
If yes to either appetite change or body weight change, code Yes.  
 bDid you have trouble sleeping nearly every night (difficulty falling asleep, waking up in the middle of the night, early morning wakening or sleeping excessively)?NoYes
 cDid you talk or move more slowly than normal or were you fidgety, restless or having trouble sitting still almost every day?NoYes
 dDid you feel tired or without energy almost every day?NoYes
 eDid you feel worthless or guilty almost every day?NoYes
 fDid you have difficulty concentrating or making decisions almost every day?NoYes
 gDid you repeatedly consider hurting yourself, feel suicidal or wish that you were dead?NoYes
Are 5 or more answers (A1-A3) coded Yes?NoYes
 Major depressive episode, current
If a patient has a current major depressive episode, continue to A4. Otherwise, continue to Table 1-6, B1.  
A4
 aDuring your lifetime, did you have other episodes of two weeks or more when you felt depressed, or uninterested in most things, and had most of the problems we just talked about?NoYes
 bIn between two episodes of depression, did you ever have an interval of at least two months without any depression and any loss of interest?NoYes
 Major depressive episode, recurrent
Diagnostic method
If either A1 or A2 are coded Yes and five or more answers of the nine questions from A1 to A3 are coded yes = major depressive disorder [RIGHTWARDS ARROW]Major depressive disorders were handled by the departments of neuropsychiatry or psychosomatic medicine.  
If both A1 and A2 are coded No and less than 5 of the answers of the nine questions from A1 to A3 are coded Yes [RIGHTWARDS ARROW]Move to ‘Dysthymic disorders’ (Table 1-6).  

Major depressive disorders are the most common form of depression and show a prevalence of 5–6% of the general population (3–4% of men). The test application of this questionnaire in 92 first-visit outpatients with andropause in a total of nine medical institutions nationwide in 2004 resulted in the diagnosis of 44 people (47.8%) with major depressive disorders. In people in their sixties, major depressive disorders were diagnosed in only about 20%, but in those in their forties and fifties, the figure was about 60%. Therefore, it appears that in addition to major depressive disorders as a complication of LOH, many patients, especially middle-aged ones, visit outpatient clinics for andropause among patients with major depressive disorders that are not associated with LOH.

Procedures for structured interviews using M.I.N.I. for dysthymic disorders are shown in Table 1-6. When the diagnosis of ‘Major depres sive episode – Current’ is made as noted at the top of the page, this diagnosis is not considered.

Table 1-6.  Dysthymic disorders – The Mini-International Neuropsychiatric Interview (M.I.N.I), Japanese version 5.0.0 (2003), Modified
If the patient's symptoms currently meet criteria for a major depressive episode, do not explore this module.
B1 Have you felt sad, low or depressed most of the time for the last two years?NoYes
B2 Was this period interrupted by your feeling OK for two months or more?NoYes
B3 During this period of feeling depressed most of the time:NoYes
aDid your appetite change significantly?NoYes
bDid you have trouble sleeping or sleep excessively?NoYes
cDid you feel tired or without energy?NoYes
dDid you lose your self-confidence?NoYes
eDid you have trouble concentrating or making decisions?NoYes
fDid you feel hopeless?NoYes
Are two or more B3 answers coded yes?NoYes
B4 Did the symptoms of depression cause you significant distress or impair your ability to function at work, socially or in some other important way?NoYes
Is B4 coded Yes?NoYes
Dysthymic disorder current
Diagnostic method
Dysthymic disorder (not major depressive disorder, but pathological depressed state continues for a long time) [RIGHTWARDS ARROW]Handled by the departments of neuropsychiatry or psychosomatic medicine.
If B1 is coded No, B2 is coded Yes, or less than two of the answers of the six questions from B3 is coded Yes = Not dysthymic disorder
If B1 is coded Yes, B2 is coded No, two or more of the answers of the six questions from B3 are coded Yes, and B4 Yes = Diagnosed as dysthymic disorder

The prevalence of dysthymic disorders is 10% of patients with major depressive disorders in the general population, but it is higher in middle-aged and elderly men. When testosterone levels were compared among groups with major depressive disorders, dysthymic disorders or healthy individuals in elderly men 60 years of age or older, it was reported that only the group with dysthymic disorders showed low levels. When the fact that major depressive disorders were few in men in their sixties visiting outpatient clinics for andropause as described above is also taken into consideration, it appears possible that dysthymic disorders are more closely related to LOH than major depressive disorders. Therefore, when symptoms such as a dejected mood occur and the diagnostic criteria for major depressive disorders are not met, it is necessary to consider a diagnosis of dysthymic disorders.

3) Severity assessment of symptoms of depression

The forms used for assessment of the severity of depression and changes in the severity of depression are basically divided into self-rating scales and observer rating scales. The self-rating scales include the Self-rating for Depression Scale (SDS), Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HAD).21,22 The most common observer-rating scale is the Hamilton Depression Rating Scale (HAM-D). None of these can be used for diagnosis and they should be used on the condition that they are applied only for assessment of the depressed state at the time of the replies. They are most useful in assessing changes in the depressed state associated with the course of treatment.

A depressed state is often only found when definite stress factors are present (usually persists for less than six months) and such cases are not very serious (they do not meet the diagnostic criteria for major depressive disorders). This is called a transient depressed state. When clinical problems arise in such patients, they are diagnosed as ‘adjustment disorders with depressed mood’ in DSM-IV. The symptom scores described here are useful in the evaluation of the severity of subjective symptoms.

4) Evaluation of ADL

Activities of daily living (ADL) are an important indicator of the mental and physical health status of the elderly. The Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence (Table 1-7) is useful for evaluating independent activity levels in the elderly living in the community.23 The Index consists of three factors: material self-reliance (questions 1–5), intellectual activeness (questions 6–9) and social role (questions 10–13). There are a total of 13 questions (5, 4 and 4, respectively). This is considered useful in assessment of delayed symptoms of LOH.

Table 1-7.  Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence
These questions concern daily activities. Reply to the following questions by encircling either Yes or No. Please answer all questions.
(1)Can you go out alone using a bus or train? . . .  . . .  . . .  . . . .1. Yes2. No
(2)Can you purchase your own daily necessities? . . .  . . .  . . .  . . . 1. Yes2. No
(3)Do you prepare your own food? . . .  . . .  . . .  . . .  . . . ..1. Yes2. No
(4)Can you pay your bills? . . .  . . .  . . .  . . .  . . .  . . .  . . . 1. Yes2. No
(5)Can you handle your bank or post office account by yourself? . . .  . . . 1. Yes2. No
(6)Do you prepare documents concerning your pension, etc.? . . .  . . . .1. Yes2. No
(7)Do you read the newspaper? . . .  . . .  . . .  . . .  . . .  . . . .1. Yes2. No
(8)Do you read books or magazines? . . .  . . .  . . .  . . .  . . . ..1. Yes2. No
(9)Are you interested in articles or programs about health? . . .  . . . ..1. Yes2. No
(10)Do you visit the homes of friends? . . .  . . .  . . .  . . .  . . . ..1. Yes2. No
(11)Do you discuss matters with your family or friends? . . .  . . .  . . . .1. Yes2. No
(12)Can you visit people who are sick? . . .  . . .  . . .  . . .  . . . 1. Yes2. No
(13)Do you try to talk to young people? . . .  . . .  . . .  . . .  . . . ..1. Yes2. No

[3] Treatment

  1. Top of page
  2. Introduction
  3. [1] Definition of LOH
  4. [2] Diagnosis
  5. [3] Treatment
  6. [4] Adverse reactions of androgen replacement therapy (ART) and their monitoring
  7. [5] Assessment after treatment
  8. References

1 Usefulness of androgen replacement therapy (ART)

Androgens have many important physiological activities in men and they have affects on the muscle, bone, central nervous system, prostate gland, bone marrow and sexual function.

  • 1
    Actions related to sexual function include maintenance of sexual desire, ejaculation and erectile action.
  • 2
    A relation with maintenance of cognitive power and emotion is suggested but the actual relation remains unclear.
  • 3
    Reported actions on the muscles include enhanced muscle strength24 and increased muscle mass and muscle strength.25
  • 4
    Actions on the bone include promotion of osteogenesis, and inhibition of bone resorption. Part of the bone mass maintenance action of testosterone occurs via the action of estrogen converted in the body. Many reports24,26–30 have given an increase in bone mineral density as an effect of ART on bone.
  • 5
    The action on erythrocyte production involves a stimulation effect on erythrocyte production. In clinical studies, it was reported that hematocrit increased 2.0–5.0% during ART, above the normal value of 6–25%.27,30–35 However, no significant increase in hematocrit was found when testosterone was administered percutaneously.
  • 6
    The effects on lipids and body fat include a decrease in body fat due to ART.24,26,33 Total cholesterol and LDL cholesterol tend to decrease.
  • 7
    In interventional research on coronary artery disease using testosterone, it was reported that electrocardiographic ST segment depression due to exercise was improved by ART in patients with coronary artery disease.36–38 In short-term research, administration at the time of attacks was ineffective and had no effect on the number of attacks. It was also reported that the number of attacks could be decreased and the tolerated level of exercise increased. However, it is not clear if ART is connected with the prevention of the onset of coronary artery disease.

2 Indications for ART (Table 1-8)

Table 1-8.  Indications of androgen replacement therapy (ART)
 Men over 40 years of age with the Late-onset Hypogonadism signs and symptoms and free testosterone blood levels as follows.
Less than 8.5 pg/mLART is first line therapy.
8.5 pg/mL to 11.8 pg/mLBased on severity of signs and symptoms, ART is one treatment option after the risks and usefulness have been explained to the patient.
11.8 pg/mL and higherART is not performed and the following treatment is considered based on the symptoms.
• Sexual function symptoms: phosphodiesterase type 5 (PDE5) inhibitor
• Mental and psychological symptoms: consultation with a neuropsychiatrist or psychosomatic physician and administration of antidepressants or antianxiety drugs
• Physical symptoms: consultation with a specialist on osteoporosis, drug therapy and guidance on life style improvements for reduced muscle strength
  • 1
    ART is indicated for men over the age of 40 with signs and symptoms of LOH when there is a drop in the free testosterone blood level.
  • 2
    ART is first-line treatment when the free testosterone blood level is less than the 8.5 pg/mL, the mean−2SD of men in their twenties.11
  • 3
    ART should be considered for men with a free testosterone level of less than 11.8 pg/mL, 70% of the mean value (16.8 pg/mL) of men in their twenties (YAM value), i.e. greater than 8.5 and less than 11.8 pg/mL, which tends to be deficient but is within the normal range. Based on the severity of signs and symptoms, ART is a treatment option after the risks and usefulness of ART have been explained to the patient.
  • 4
    ART is not performed when the free testosterone blood level is 11.8 pg/mL or higher, and the following treatment is considered based on the symptoms. When sexual function symptoms are severe, a PDE5 inhibitor is administered. When psychological symptoms are severe, a neuropsychiatrist or psychosomatic physician is consulted and antidepressants or antianxiety agents are administered. When physical symptoms are severe, if osteoporosis is suspected, consultations are held with a specialist and drug therapy is considered, and for reductions in muscle strength, guidance is given on lifestyle improvements.

3 ART exclusion criteria

ART is not performed in patients with the diseases or conditions shown in Table 1-9.

Table 1-9.  Androgen replacement therapy (ART) exclusion criteria
  1. PSA, prostate specific antigen.

• Prostate cancer• Polycythemia
• Pretreatment PSA values of not less than 2.0 ng/mL• Severe hepatic dysfunction
Treatment should be performed with caution when the PSA value is not less than 2.0 and less than 4.0 ng/mL• Severe renal failure
• Congestive heart failure
• Moderate to severe benign prostatic hyperplasia• Severe hypertension
• Breast cancer• Sleep apnea

4 ART protocols

1) Protocols

The following three ART protocols are recommended.

  • 1
    Testosterone enanthate is administered intramuscularly at 125 mg each time every two or three weeks or 250 mg each time every three to four weeks.

Since the maximum testosterone blood levels are reached in about four to seven days after administration, caution is required because of the possibility that the serum testosterone levels will exceed normal values and reach a non-physiological level when the single dose is high. It is recommended that blood be collected once about four to seven days after administration and the concentration of free testosterone in the blood be measured.

  • 2
    Human chorionic gonadotropin (hCG) is administered intramuscularly at 3000–5000 units each time once or twice a week or every two weeks.

The hCG test is performed on patients with normal LH blood levels and if the response of testosterone in the blood is good, hCG is administered.39 The advantage is that changes in blood testosterone are relatively small when compared with those of testosterone enanthate, and the disadvantage is that many administrations are required.

  • 3
    Testosterone ointment is applied at a dose of 3 g each time once or twice a day on the skin of the scrotum (equivalent to 3 mg of testosterone each time). Administration is easy and stable testosterone concentrations in the blood are obtained.40
2) Treatment period

With all methods, evaluation is performed every three months after the start of treatment. If effects are observed, treatment is continued with caution concerning adverse reactions.

3) Contraindicated concomitant medication

Contraindicated concomitant medication for male testosterone enanthate are warfarin potassium and other anticoagulants. Since the action of anticoagulants is intensified by concomitant administration, caution is required including reducing the dose of the anticoagulants.

[4] Adverse reactions of androgen replacement therapy (ART) and their monitoring

  1. Top of page
  2. Introduction
  3. [1] Definition of LOH
  4. [2] Diagnosis
  5. [3] Treatment
  6. [4] Adverse reactions of androgen replacement therapy (ART) and their monitoring
  7. [5] Assessment after treatment
  8. References

1 ART adverse reactions and complications

Androgens are steroid hormones that act on many organs and tissues. Risks that should be considered when performing ART include cardiovascular diseases, lipid metabolism disorders, polycythemia, fluid retention, prostatic hyperplasia, prostate cancer, hepatotoxicity, sleep apnea, gynecomastia, acne, testicular atrophy, infertility, and changes in behavior or mood.3,41

1) Adverse reactions
  • 1
    Cardiovascular diseases

It has been reported that the prevalence of coronary artery disease is high in patients with hypogonadism.42,43 However, no effects of long-term ART on the cardiovascular system have been confirmed and cardiovascular testing is required depending on clinical symptoms.

  • 2
    Lipid metabolism

No adverse effects on lipid metabolism have been found with ART when blood testosterone levels do not exceed the physiological range during treatment.44,45 Decreases in blood levels of HDL cholesterol have been observed at high doses.44

  • 3
    Polycythemia

Polycythemia that requires suspension of thrombectomy or cessation of ART is observed in 24% of patients with hypogonadism treated with ART.46 During treatment, it is necessary to monitor polycythemia by periodic blood tests. The criteria for polycythemia are red blood cell (RBC) counts 6 × 106/μL or more, hemoglobin of 18 g/dL or more and hematocrit of 53%. In such conditions, adjustment of ART intervals and consultations by a hematologist are needed.

  • 4
    Hepatotoxicity

Hepatic dysfunction has been found in about one third of patients administered testosterone orally,47 but hepatic dysfunction due to oral administration of testosterone undecanoate or intramuscular administration of testosterone enanthate is rare.48

  • 5
    Sleep apnea

Since ART can exacerbate sleep apnea,49,50 ART is contraindicated for patients with sleep apnea.

  • 6
    Other adverse reactions

Acne, increased body hair and flushing have been observed but they are not significant adverse reactions.51

2) Monitoring of ART adverse reactions (Table 1-10)
Table 1-10.  Monitoring to avoid androgen replacement therapy (ART) adverse reactions
CourseMonitored items
  1. PSA, prostate specific antigen.

Before treatment• General examination and laboratory tests
• Questionnaire on voiding conditions
• Checking for sleep apnea
• Serum PSA
After treatment• Optimal dose set after 1–2 months based on clinical symptoms
• Blood tests (after 2–4 weeks, 3 months, 6 months and 12 months and once a year thereafter)
• Monitoring of voiding conditions and sleep apnea
• Serum PSA

At baseline, physical examination and laboratory tests, an evaluation of voiding conditions using IPSS and history of sleep apnea should be ascertained. In hematology, hemoglobin, hematocrit and RBC count are especially important. In blood chemistry, TC, TG, HDL-C, LDL-C, GOT, GPT, ALP, γ-GTP, FBS and HbA1c must be tested. Routine urinalysis including urinary sugar must be checked periodically. Blood tests should be checked two to four weeks, three months, six months and twelve months after the initiation of the treatment and once a year thereafter. Treatment must be discontinued or the dose is adjusted as required based on the test values. Voiding conditions and sleep apnea should be monitored and if abnormalities are found, treatment is discontinued or doses should be reduced, and then referred to specialists as required. Periodic cardiovascular examinations are not necessary, but when abnormalities are discovered by tests performed, ART should be discontinued and an evaluation by a specialist is needed.

2 ART and prostate disease

Caution is required in relation to prostate disease, which is a risk for ART. ART is absolutely contraindicated in cases of prostate cancer and relatively contraindicated for prostatic hyperplasia. ART and prostate disease are discussed from three standpoints: prostatic hyperplasia, prostate cancer and the serum prostate specific antigen (PSA) value.

1) Effect of ART on prostatic hyperplasia and dysuria

In comparison with a placebo group, the ART group showed no worsening of voiding symptoms or complications due to prostatic hyperplasia.24,30,52–57 In short-term ART (maximum of 36 months) in elderly men, no clear changes in prostate size, urinary flow rate or IPSS were reported.58 However, the prostate is known to be androgen dependent59 and prostate weight usually decreases with antiandrogen therapy. It is necessary to consider enlargement of the prostate due to ART.

2) Relation between ART and prostate cancer

There is little evidence that ART causes prostate cancer but there are case reports suggesting the progression from latent cancer to clinical cancer.60,61 In prospective studies,27,28,44,57,62 prostate cancer appeared in five out of 461 patients (1-%) given ART for 6–36 months, but this was the same as the general prevalence. However, the effects of long-term treatment for more than 36 months are unclear. Therefore, the serum PSA value must be carefully monitored as described below.

3) ART and Serum PSA values

Appropriate Serum PSA monitoring is important for early discovery of prostate cancer. The PSA criteria for ART are shown in Figure 4.

image

Figure 4. Evaluation of PSA values at start of and during ART.

Download figure to PowerPoint

  • 1
    PSA of less than 2.0 ng/mL is recommended as the standard value for indicating ART. There is no evidence for this standard value. One report concluded that a standard value of 4.0 ng/mL is generally appropriate41 while another report concluded that ART is not performed at 3.0 ng/mL. In addition, there are reports that latent cancer63,64 and highly atypical cancer64,65 are likely to occur in the low testosterone group. In this Manual, the PSA standard value was set at a low value.
  • 2
    ART should be considered after a careful investigation when PSA is greater than 2.0 and less than 4.0 ng/mL. In Western countries, ART is sometimes performed after prostate biopsies.54
  • 3
    When PSA is greater than 4.0 ng/mL or when other findings of suspected prostate cancer are obtained, a specialist should be consulted.
  • 4
    ART should be discontinued and a specialist consulted when PSA increases by greater than 0.5 ng/mL at six months or greater than 1.0 ng/mL at one year after start of ART.

[5] Assessment after treatment

  1. Top of page
  2. Introduction
  3. [1] Definition of LOH
  4. [2] Diagnosis
  5. [3] Treatment
  6. [4] Adverse reactions of androgen replacement therapy (ART) and their monitoring
  7. [5] Assessment after treatment
  8. References

Treatment of LOH is usually continued for a long time. When ART is performed, blood levels of testosterone basically increase in all patients. It is necessary to assess the signs and symptoms of LOH associated with improvements in blood testosterone levels as treatment effects. Since evidence has still not been established for the therapeutic effects on LOH Syndrome in particular, it is necessary to accumulate evidence by global evaluations. This is the objective of this Manual.

The therapeutic effects are usually evaluated at least every three months at one year after the start of treatment and the intention of the patient, including continuing or discontinuing treatment, is confirmed. When treatment is performed for more than one year, it is important to observe variations in the symptoms periodically. In the official recommendation by ISSAM in 2002, it states ‘Observation of the course during ART is the responsibility of both the physician and the patient. The necessity of periodic evaluations of patients by physicians must be stressed and the patients must agree to follow these requirements.’ Thus, the importance of periodic evaluations by both physicians and patients is emphasized.3 This recommendation includes the statement that ‘Hormone replacement therapy is normally performed for life and observation of the course is also a lifetime duty.’ However, time is required before this point is clearly understood in Japan. At present, it cannot be stated that it is necessary to continue for the rest of the patient's life once ART is started, and therefore it is necessary for both the physician and patient to have a common understanding of the treatment period. When adverse reactions appear, there are cases when treatment should be discontinued even though the treatment was found to be effective.4–7

References

  1. Top of page
  2. Introduction
  3. [1] Definition of LOH
  4. [2] Diagnosis
  5. [3] Treatment
  6. [4] Adverse reactions of androgen replacement therapy (ART) and their monitoring
  7. [5] Assessment after treatment
  8. References
  • 1
    Vermeulen A. Andropause. Maturitas 2000; 34: 515 Review.
  • 2
    Morley JE. Andropause, testosterone therapy, and quality of life in aging men. Cleve. Clin. J. Med. 2000; 67: 8802.
  • 3
    Morales A, Lunenfeld B. International society for the study of the aging male: investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. Aging Male 2002; 5: 7486.
  • 4
    Nieschlag E, Swerdloff R, Behre HM et al. Investigation, treatment, and monitoring of Late-onset Hypogonadism in Males: ISA, ISSAM, and EAU recommendations. J. Androl. 2006; 27: 1357.
  • 5
    Nieschlag E, Swerdloff R, Behre HM et al. International Society of Andrology (ISA); International Society for the Study of the Aging Male (ISSAM); European Association of Urology (EAU): investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur. Urol. 2005; 48: 147.
  • 6
    Nieschlag E, Swerdloff R, Behre HM et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Int. J. Androl. 2005; 28: 1257.
  • 7
    Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of late-onset hypogonadism in males: scientific background and rationale. Aging Male 2005; 8: 5974 Review.
  • 8
    Kazuo C et al. Investigation of hypothalamic-pituitary disorders. Guideline for the diagnosis and treatment of adult growth hormone deficiency (in Japanese) supported by the Ministry of Health, Labour and Welfare, Japan 2005; 1214.
  • 9
    Endocrine Society: Summary from the second Annual Andropause Consensus Committee. 2002.
  • 10
    Nieschlag E, Swerdloff R, Behre HM et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 2005; 8: 568.
  • 11
    Iwamoto T, Yanase T, Koh E et al Reference ranges of total serum and free testosterone in Japanese male adults. Nippon Hinyokika Gakkai Zasshi (in Japanese) 2004; 95: 75160.
  • 12
    Orimo H, Hayashi Y, Fukunaga M et al. Osteoporosis Diagnostic Criteria Review Committee: Japanese Society for Bone and Mineral Research. Diagnostic criteria for primary osteoporosis: year 2000 revision J Bone Miner Metab. (in Japanese) 2001; 19 (6): 3317.
  • 13
    Ooi DS, Innanen VT, Wang D et al. Establishing reference intervals for DPC's free testosterone radioimmunoassay. Clin. Biochem. 1998; 31: 1521.
  • 14
    Definition and the diagnostic standard for metabolic syndrome – Committee to Evaluate Diagnostic Standards for Metabolic Syndrome. Nippon Naika Gakkai Zasshi. (in Japanese) 2005; 94:794809.
  • 15
    Heinemann LA, Saad F, Zimmermann T et al. A new ‘Aging Males’ Symptoms' (AMS) rating scale. Aging Male 1999; 2: 10514.
  • 16
    Heinemann LA, Saad F, Zimmermann T et al. The Aging Males' Symptoms (AMS) scale: update and compilation of international versions. Health Qual. Life Outcomes 2003; 1: 15.
  • 17
    Daig I, Heinemann LA, Kim S et al. The Aging Males' Symptoms (AMS) scale: review of its methodological characteristics. Health Qual. Life Outcomes 2003; 1: 77.
  • 18
    T' Sjoen G, Feyen E, De Kuyper P et al. Self-referred patients in an aging male clinic: much more than androgen deficiency alone. Aging Male 2003; 6: 15765.
  • 19
    American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR American Psychiatric Publishing 2000.
  • 20
    Sheehan DV, Lecrubier Y The Mini International Neuropsychiatric Interview (M.I.N.I.) 5.0. https://www.medical-outcomes.com/HTMLFiles/MINI/MINI.htm
  • 21
    Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr. Scand. 1983; 67: 36170.
  • 22
    Sugimori H, Yoshida K, Tanaka T et al. Relationship between erectile dysfunction, depression, and anxiety in Japanese subjects. J. Sex. Med. 2005; 2: 3906.
  • 23
    Koyano W, Shibata H, Haga H Measurement of competence in the elderly living at home Nihon koshu eisei zassi(in Japanese) 1987; 34 (3): 109114.
  • 24
    Kenny AM, Prestwood KM, Gruman CA et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J. Gerontol. A Biol. Sci. Med. Sci. 2001; 56: M266M272.
  • 25
    Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J. Am. Geriatr. Soc. 2003; 51: 10115.
  • 26
    Behre HM, von Eckhardstein S, Kliesch S et al. Long term substitution therapy of hypogonadal men with transscrotal testosterone over 7–10 years. Clin. Endocrinol. 1999; 50: 62935.
  • 27
    Snyder PJ, Peachey H, Hannoush P et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J. Clin. Endocrinol. Metab. 1999; 84: 196672.
  • 28
    Snyder PJ, Peachey H, Berlin JA et al. Effects of testosterone replacement in hypogonadal men. J. Clin. Endocrinol. Metab. 2000; 85: 26707.
  • 29
    Baulieu EE, Thomas G, Legrain S et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc. Natl. Acad. Sci. USA 2000; 97: 427984.
  • 30
    Sih R, Morley JE, Kaiser FE et al. Testosterone replacement in older hypogonadal men: A 12-month randomized controlled trial. J. Clin. Endocrinol. Metab. 1997; 82: 16617.
  • 31
    Morgentaler A, Bruning CO III, DeWolf WC. Occult prostate cancer in men with low serum testosterone levels. JAMA 1996; 276: 190406.
  • 32
    Katznelson L, Finkelstein JS, Schoenfeld DA et al. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J. Endocrinol. Metab. 1996; 81: 435865.
  • 33
    Tenover JS. Effects of testosterone supplementation in the aging male. J. Clin. Endocrinol. Metab. 1992; 75: 10928.
  • 34
    Clague JE, Wu FC, Horan MA. Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men. Int. J. Androl. 1999; 22: 2615.
  • 35
    Cherrier MM, Asthana S, Plymate S et al. Testosterone supplementation improves spatial and vertebral memory in healthy older men. Neurology 2001; 57: 808.
  • 36
    Jaffe MD. Effect of testosterone cypionate on postexercise ST segment depression. Br. Heart J. 1977; 39: 121722.
  • 37
    Rosano GM, Leonardo F, Pagnotta P et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1999; 99: 166670.
  • 38
    Webb CM, Adamson DL, de Zeiger D et al. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am. J. Cardiol. 1999; 83: 4379.
  • 39
    Tsujimura A, Matsumiya K, Takao T et al. Human chorionic gonadotropin treatment for PADAM. A preliminary report. Aging Male 2005; 8: 1759.
  • 40
    Amano T, Takemae K, Basa K et al. Circadian rhythm and pharmacokinetic profiles of free testosterone after application of testosterone ointment in healthy men Nihon seikinou gakkai zassi(in Japanese) 2005; 20: 1218.
  • 41
    Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N. Engl. J. Med. 2004; 350: 48292.
  • 42
    Zmuda JM, Cauley JA, Kriska A et al. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am. J. Epidemiol. 1997; 146: 60917.
  • 43
    English KM, Mandour O, Steeds RP et al. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur Heart J. 2000; 21: 8904.
  • 44
    Singh AB, Hsia S, Alaupovic P et al. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J. Clin. Endocrinol. Metab. 2002; 87: 13643.
  • 45
    Kouri EM, Pope HG Jr, Oliva PS. Changes in lipoprotein-lipid levels in normal men following administration of increasing doses of testosterone cypionate. Clin. J. Sport Med. 1996; 6: 1527.
  • 46
    Hajjar RR, Kaiser FE, Morley JE. Outcome of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J. Clin. Endocrinol. Metab. 1997; 82: 37936.
  • 47
    Westaby D, Ogle SJ, Paradinas FJ. Liver damage from long-term methyltestosterone. Lancet 1977; 6: 2623.
  • 48
    Bagatell CJ, Bremner WJ. Androgens in men--uses and abuses. N. Engl. J. Med. 1996; 334: 70714.
  • 49
    Schneider BK, Pickett CK, Zwillich CW et al. Influence of testosterone on breathing during sleep. J. Appl. Physiol. 1986; 61: 61823.
  • 50
    Matsumoto AM, Sandblom RE, Schoene RB et al. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clin. Endocrinol. (Oxf.) 1985; 22: 71321.
  • 51
    Wang C, Alexander G, Berman N et al. Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study. J. Clin. Endocrinol. Metab. 1996; 81: 357883.
  • 52
    Krieg M, Nass R, Tunn S. Effect of aging on endogenous level of 5α-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. J. Clin. Endocrinol. Metab. 1993; 77: 37581.
  • 53
    Dobs AS, Meikle AW, Arver S et al. Pharmacokinetics, efficacy, and safety of a permeation enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J. Clin. Endocrinol. Matab. 1999; 84: 346978.
  • 54
    Marcelli M, Cunningham GR. Hormonal signaling in prostatic hyperplasia and neoplasia. J. Clin. Endocrinol. Metab. 1999; 84: 34638.
  • 55
    Comhaire FH. Andropause: hormone replacement therapy in the aging male. Eur. Urol. 2000; 38: 65562.
  • 56
    Slater S, Oliver RTD. Testosterone: its role in development of prostate cancer and potential risk from use as hormone replacement therapy. Drugs Aging 2000; 17: 4319.
  • 57
    Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of the prostate gland. Arch. Surg. 1941; 43: 20923.
  • 58
    Morales A, Johnson B, Heaton JP et al. Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes. J. Urol. 1997; 157: 84954.
  • 59
    Perchersky AV, Mazurov VI, Semiglazov VF et al. Androgen administration in middle-aged and ageing men: effects of oral testosterone undecanoate on dihydrotestosterone, oestradiol and prostate volume. Int. J. Androl. 2002; 25: 11925.
  • 60
    Loughlin KR, Richie JP. Prostate cancer after exogenous testosterone treatment for impotence. J. Urol. 1997; 157: 1845.
  • 61
    Curran MJ, Bihrle W III. Dramatic rise in prostate-specific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 1999; 53: 4234.
  • 62
    Wang C, Swerdloff RS, Iranmanesh A et al. Testosterone Gel Study Group: transdermal testosterone gel improves sexual function, mood, muscle strengths, and body composition parameters in hypogonadal men. J. Clin. Endocrinol. Metab. 2000; 85: 283953.
  • 63
    Heikkila R, Aho K, Heliovaara M et al. Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study. Cancer 1999; 86: 31215.
  • 64
    Thompson IM, Goodman PJ, Tangen GM et al. The influence of finasteride on the development of prostate cancer. N. Engl. J. Med. 2003; 349: 21524.
  • 65
    Goodman PJ, Tangen CM, Crowley JJ et al. Implementation of the Prostate Cancer Prevention Trial (PCPT). Control. Clin. Trials 2004; 25: 20322.