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Hormonal replacement therapy and aging: Asian practical recommendations on testosterone supplementation

Young Chan Kim

Yonsei University College of Medicine, Korean Sexual and Men's  Health Center, 135-911 Seoul, Korea

Asian J Androl 2003 Dec; 5: 339-344


Keywords: hormone alteration; recommendation; testosterone supplementation; aging male
Abstract

Profound and diffuse alterations in the production of gonadal and adrenal androgens as well as growth hormone are associated with aging. To convey this concept more appropriately, partial endocrine deficiency in the aging male (PEDAM) was introduced as a term for the phenomenon of hormonal alterations in the aging male. Hormones responsible for some of the manifestations associated with male aging are testosterone, growth hormone, dehydroepiansdrosterone (DHEA), melatonin, thyroid hormones and leptin. Of these, testosterone has been widely investigated and its beneficial and adverse effects on male bodily systems are relatively well established. However, a serious body of confusion and misunderstandings surrounding the diagnosis, treatment and monitoring of men suspected of having androgen deficiency has been raised. Therefore, it is timely to provide practical criteria for diagnosis and treatment to avoid misconception about the use of testosterone in the aging male. To provide an understanding and information of the issues, the following headings are summarized: (1) Important clinical consideration on testosterone supplementation in the aging male; (2) Asian practical recommendations on testosterone supplementation in the aging male.

1 Introduction

The age related changes in men over 50 years of age have created an intense world-wide interest in hormonal supplementation in the aging male [1]. Profound and diffuse alterations in the production of gonadal and adrenal androgens as well as growth hormone are associated with aging. To convey this concept more appropriately, partial endocrine deficiency in the aging male (PEDAM) [2] was introduced as a term for the phenomenon of hormonal alterations in the aging male.

Hormones shown to alter with male aging are testosterone, growth hormone, dehydroepiansdrosterone (DHEA), melatonin, thyroid hormones and leptin [3]. All of these hormones are responsible for some of the manifestations associated with aging. In addition, it has been suggested that these hormones exert their actions by interacting directly and indirectly with relevant hormones. There is some evidence suggesting the modulation of pineal melatonin production by GnRH, gonadotropins and sex steroids [4], the suppression of leptin by testosterone [5] and the activation of the somatotropic axis by testosterone [6]. Therefore, understanding these hormones is very pivotal for the evaluation and treatment of the aging male.

However, well-organized clinical experience on these hormones is still very limited and the studies are not yet definitive. Therefore, it is premature to describe clinical guidelines for all these hormones. On the other hand, testosterone has been widely investigated and its beneficial and adverse effects on male bodily systems are relatively well established. In this chapter, information on testosterone supplementation is described.

2 Important clinical considerations on testosterone supplementation in aging male

2.1. Candidates for supplementation

The existence of the clinical manifestations of hypogonadism together with biochemical support is a clear indication for testosterone supplementation [3]. Clinically, a decrease in muscle mass and strength, decrease in bone mass and increased abdominal fat mass are easily identified, whereas symptoms such as decreased libido, memory loss or decreased general well-being are more difficult to discern.

Only men with subnormal or low-normal levels of testosterone are candidates for androgen substitution [7]. The final decision on whether or not to treat will depend upon the balance between expected benefits and potentially serious adverse effects. If testosterone therapy is clearly indicated, it can be given to enhance the patients' quality of life, even if they are of advanced age [8].

2.2 Expected benefits

Testosterone supplementation in older patients has been shown to provide beneficial effects on bone density and bone turnover, muscle mass, strength and body composition and possibly an improved sense of well-being, energy level, sexual function and libido [9, 10, 11]. But in hypogonadal men, bone mineral density remains low after long-term testosterone replacement [12]. Even though older men may have successful erections, their sexual desire, mood and general behavior are very underactive and these aspects of sexual function can be expected to improve with testosterone supplementation [13]. Furthermore, the intensity of orgasms and ejaculations might also be expected to improve [14].

2.3 Assessment and diagnostic tests

The diagnosis of hypogonadism can be made based on the presence of symptoms and signs of androgen deficiency with confirmation by laboratory testing.

2.3.1 Past history, medical history, physical Examination and blood tests

A full medical history looking for the presence of diabetes mellitus, hypertension, smoking, endocrine disorders, heart disease, sleep-related apnea and other medications should be undertaken when testosterone supplementation is considered [15]. The physical examination and tests conducted prior to initiating testosterone therapy should include measurement of body weight, pulse rate, blood pressure, complete blood cell count, urine analysis and blood chemistry parameters. The physical manifestations related androgen deficiency also should be assessed.

2.3.2 Plasma hormone determination

It has been suggested that measurement of testosterone is reserved to the patients with positive physical findings of hypogonadal symptoms. However, determination of total testosterone is strongly recommended for all patients with erectile dysfunction as the first line endocrine evaluation, because libido, the principal symptom of hypogonadism, may be a nonspecific finding and physical examinations is usually normal in postpubertal hypogonadism. While hormonal status is usually evaluated by measurements of serum hormone levels, determination of total testosterone has been regarded as a universally accepted diagnostic method of serum hormonal level to date [16]. However, there are increasing evidences that the serum concentration of total testosterone may not be an accurate marker for the levels that exert their action on target organs. Androgen deficiency can be better demonstrated by measuring bioavailable testosterone, i.e. free and albumin-bound fractions of circulating testosterone. Therefore, measuring total testosterone in aging men may not be adequate to determine whether they have testosterone deficiency as levels of circulating SHBG increase with age and measurement of bioavailable or free fractions of testosterone is needed to correctly diagnose hypogonadism in men over age 50 [17]. To make accurate diagnosis of hypogonadism, more reasonable and acceptable diagnostic criteria using bioavailable testosterone should be established in the future especially in the aging male.

With respect to evaluation of bioavailable testosterone, Vermeulen and Kaufman [18] suggested the calculation method in obtaining the concentration of serum free testosterone and comparison of the results from all available methods of evaluating bioavailable testosterone, such as the concentration of free testosterone obtained by equilibrium dialysis, calculation of free testosterone from total testosterone and immunoassayed sex hormone-binding globulin (iSHBG) concentrations, direct immunoassay of free testosterone with a labeled analog, the free androgen index (FAI = the ratio 100T/iSHBG) and the fraction of serum testosterone not precipitated by 50 % ammonium sulfate concentration (non-SHBG-T levels). They concluded that the concentration of free testosterone obtained by calculation from testosterone and SHBG appears to be a rapid, simple and reliable index of bioavailable testosterone comparable to the concentration of free testosterone obtained by equilibrium dialysis and suitable for clinical routine.

If clinical situation is difficult to get bioavailable testosterone at first patient's visit, total testosterone could be measured. When patients are found to have a testosterone level which is low or at the lower borderline of normal range, a repeat testosterone measurement is generally recommended because there is evidence that a substantial number of patients with erectile dysfunction have a low plasma testosterone level at the first determination but a normal level when the test is repeated [19]. At this time, measurements of SHBG, LH and prolactin can be performed in order to clarify the screening testosterone level and to calculate bioavailable testosterone from testosterone and SHBG [16].

Measuring gonadotropins is necessary to avoid missing many conditions of compensated testicular failure in which the plasma testosterone level is usually normal [20]. Another reason for measuring gonadotropins is to detect secondary hypogonadism, which requires specific diagnosis and treatment. However, it should be realized that in hypogonadism of elderly males, plasma LH levels are often not raised [17]. A single LH determination is preferable in terms of cost-effectiveness [16]. However, it has been suggested that measurement of both LH and FSH can be helpful in certain clinical situations [21]. The routine use of prolactin determinations is less well-defined, because isolated hyperprolactinemia is rare and most patients with hyperprolactinemia have abnormally low testosterone levels. Patients who present with symptoms of hyperprolactinemia such as decreased libido and headache with depressed testosterone levels are suggestive of prolactin abnormality [16].

To what extension the laboratory tests should be applied to evaluate the causes of secondary hypogonadism in the aging male is one of the area that require further elucidation.

2.3.3 Prostate evaluation

It is generally accepted that the most effective method for early detection of prostate cancer is the combination of prostate-specific antigen (PSA) determination and digital rectal examination (DRE) [22]. However, in a study in which ultrasound-guided prostate needle biopsy was performed in 77 patients with low total or free testosterone levels but normal PSA levels (4 ng/mL or less) and DRE results, prostatic cancer was identified in 14 % of the entire group and 29 % of those older than 60 years[19]. Thus, the possible presence of prostatic cancer should still be borne in mind despite normal PSA and DRE findings. Therefore, it has been suggested that transurethral ultrasonography (TRUS), with or without biopsy of the prostate, might be performed before starting hormonal therapy in men over 60 years of age. However, this practice cannot be enthusiastically embraced because screening of prostate cancer with TRUS is unreliable and random ultraguided biopsy is unproven [17]. Further studies on prostatic assessment and hormonal treatment of men with low testosterone levels are required.

2.3.4 Other Tests

Questionnaires are available for evaluating climacteric symptoms, the patient's sense of well-being and the sexual function in aging men. In addition, physicians may measure the waist-hip ratio for evaluation of body composition. A lipid profile [including triglyceride, high-density lipoprotein cholesterol (HDL-C) and total cholesterol] and liver function tests are recommended for assessing the patient's risk status.

2.4 Follow-up

Periodic follow-up is mandatory during testosterone supplementation to detect treatment-related adverse effects as early as possible. However, the appropriate follow-up interval is not well defined. In a review documenting 10 years of experience with oral testosterone undecanoate therapy, one authority advocated 3-month follow-ups during the early part of treatment followed by 6-monthly follow-ups [24]. Others have suggested a 6-monthly follow-up interval for 2 years after initiating treatment [14]. During the first month after initiation of treatment, patients should be followed to assess whether the desired testosterone level is being achieved, whether complications such as acne or other adverse effects are being experienced and whether climacteric symptoms are improved with supplementation. After 1 month, a few appropriate questions, if needed, a physical examination and a plasma testosterone determination can be undertaken. At 3 months after initiating treatment, changes in climacteric symptoms should be assessed and monitoring for complications with a complete blood cell count and clinical laboratory tests, as well as PSA measurement and DRE for prostatic evaluation. Plasma testosterone levels can also be checked at this time to determine whether exogenous testosterone is influencing the intrinsic androgen secretory capacity.

At 6 months after initiating treatment, the clinical laboratory tests carried at 3 months should be repeated and, in addition, a liver function test, urinanalysis and PSA determination should be performed. The follow-up can be repeated every 6 months for the next 1.5 years. At least 1.5 to 2 years of monitoring is needed to assess PSA velocity (PSAV), which is a highly specific marker for the presence of prostate cancer; three PSA measurements might be optimal during this period to minimize short-term within-patient variability between measurements [23]. Considering that occult prostate cancer can be missed in men with normal DRE findings and normal PSA levels, physicians should do everything possible to detect preclinical carcinoma of the prostate. In this regard, PSA measurement is recommended at 6-month intervals during treatment, especially in men over 50 years of age. After this period, annual follow-up is recommended. Even if supplementation is ceased less than 6 months after initiating testosterone treatment, PSA measurement is recommended after discontinuing treatment.

An increase in PSA of 2.0 ng/mL at any time or an increase more than 0.75 ng·mL-1·year-1 over 2 year period requires further exploration [25], while an increase in hematocrit over 54 % [26] or unfavorable changes in the lipid profile require a reduction of the substitutive dose or discontinuation of treatment. Androgen substitution should be continued lifelong, unless adverse effects appear or the patient is no longer concerned by the signs and symptoms of hypogonadism.

3 Asian practical recommendations on testosterone supplementation in aging male

3.1 Candidates for testosterone supplementation

3.1.1 Clinical manifestations

The existence of the clinical manifestations of hypogonadism together with biochemical support is a clear indication for testosterone supplementation. A clinical picture of androgen deficiency in the aging male includes the following:

a) Diminished sexual desire and erectile quality;
b) Changes in mood with concomitant decreases in intellectual activity, spatial orientation ability, fatigue, depressed mood and irritability;
c) Decrease in lean body mass with associated diminution in muscle volume and strength;
d) Decrease in body hair and skin alterations;
e) Decreased bone mineral density resulting in osteopenia and osteoporosis;
f) Increase in visceral fat;
g) Development of gynecomastia.

3.1.2 Only men with low or borderline normal serum testosterone are suitable candidates for testosterone supplementation.

3.1.3 The following conditions are contraindicated from testosterone supplementation:

a) PAS level higher than 4.0 ng/dL;
b) Abnormal findings of DRE in consistency or palpable prostate nodule;
c) Polycythemia;
d) Severe cardiac insufficiency.

3.1.4 Patients with the following conditions may receive testosterone replacement therapy, but careful monitoring is mandatory:

a) Respiratory difficulties;
b) Severe snoring at night;
c) Large amount of sputum longer than 3 months per year;
d) Low Urinary Tract Symptoms (LUTS);
e) Hyperlipidemia.

3.2 Examination and assessments

The following assessment and lab tests may be performed in all men before starting testosterone replacement therapy:

3.2.1 A thorough past and medical history, including the life style that can effect the hormonal milieu;

3.2.2 A careful physical examination, including measurement of height, weight, pulse rate, blood pressure and waist hip ration (WHR);

3.2.3 Questionnaires to assess the climacteric symptoms, sexual function and quality of life;

3.2.4 Lab tests, including urinalysis, CBC and blood chemistry;

3.2.5 Prostate evaluation with measurement of PSA and DRE;

3.2.6 The most reliable parameter to establish the presence of hypogonadism is the measurement of bioavailable testosterone or alternatively, a calculated free testosterone. If it is difficult to get bioavailable testosterone at the patient's first visit, total testosterone could be measured. When the level of total serum testosterone is low or borderline, repeated measurements should be performed together with SHBG, LH, and prolactin to evaluate the bioavailable testosterone and the status of hypothalamic-pituitary-gonadal axis;

3.2.7 The following measurements could be applied in special situations: determination of FSH, special lab test for identifying secondary hypogonadism, evaluation of bone metabolism such as bone markers and bone mineral density and determination of muscle power and body composition.

3.3 Testosterone preparations

Currently available preparations of testosterone (with the exception of the alkylated ones) such as oral unde-canoate, transdermal preparation and injectable esters are safe and effective [3]. Physicians are advised to avoid supraphysiological blood levels of testosterone as the purpose of supplementation is to bring and maintain serum testosterone levels within the physiological range[3].

3.4 Recommended follow-up protocol

In order to regularly monitor the patients, they are advised to visit the out-patient clinic every month. Laboratory tests for detecting complications and adverse reactions are needed every 3 months during testosterone supplementation.

3.4.1 The first month

To assess whether the desired testosterone level is achieved, whether complications or other adverse effects are experienced and whether climacteric symptoms are improved. A few appropriate questionnaires, a physical examination and a plasma testosterone determination may be taken. The time of collection of blood sample should be correlated with the type of testosterone administered.

3.4.2 The third month

a) repeat the evaluations done at the first month. For detecting adverse reactions, physicians can measure CBC and PSA and perform DRE;
b) measurement of lipid profile, muscle mass and body fat may be performed.

3.4.3 The Sixth month

a) repeat the evaluations and clinical laboratory tests carried out at the 3rd month and, in addition, a liver function test and urinanalysis may be performed;
b) measurement of the bone marker may be done.

3.4.4 The twelvth month

a) repeat all the assessments at the 6th month, including the performance of questionnaires and DRE and the determination of testosterone, CBC, PSA, urinalysis and liver function test. Additional tests include the evaluation of blood sugar by measuring the fasting blood sugar or hemoglobin A1C;
b) measurement of bone mineral density may be done.

3.4.5 Subsequent follow up: every 6 months for 2 years then annually.

3.5 Discontinuation and adjustment of dosage

The conditions necessitate testosterone dose-adjustment or discontinuition:

3.5.1 Absolute indication:

a) development of cardiac symptoms or heart disease;
b) increase of PSA more than 4.0 ng/dl;
c) abnormal findings DRE in consistency or palpable prostate nodule;
d) polycythemia or hematocrit greater than 54%.

3.5.2 Relative indication:

a) adverse reactions of the agents (e.g skin complication);
b) aggravation of LUTS;
c) weight gain due to edema;
d) abnormal findings in lipid profile;
e) development of negative behavioral patterns.

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Correspondence to: Professor Young Chan Kim, Yonsei University College of Medicine; Director, Korean Sexual and Men's Health Center, Han Central Bldg., 646-7 Yoksam-dong, Kangnam-ku 135-911, Seoul, Korea.
Tel: +82-2-568 5353, Fax: +82-2-568 5343
E-mail: youngkim2004@kornet.net
Received 2003-06-30 Accepted 2003-09-15