The International Society for the Study of the Aging Male (ISSAM) recommends that a diagnosis be based on a patient's total testosterone (TT), calculated free testosterone (cFT), or calculated bioavailable testosterone (cBT) for partial androgen deficiency of the aging male (PADAM). The purpose of this study was to confirm whether hypogonadism of patients with PADAM is related to symptoms and clarify which criteria of testosterone recommended by ISSAM is suitable for Japanese patients. A total of 90 patients with PADAM symptoms were included in this study. Endocrinologic profiles were reviewed as appropriate, and PADAM symptoms were judged by means of several questionnaires. Laboratory values and symptoms were compared between patients with and without hypogonadism. Even when any criterion of testosterone was used for diagnosis of hypogonadism, AMS (total and subscales), IIEF-5, or SDS scores of PADAM symptoms did not differ significantly between patients classified as having and not having hypogonadism. No other endocrinologic variables than testosterone differed significantly between them, either. PADAM symptoms are not related to testosterone level and it is still obscure whether ISSAM's criterion can be adopted for Japanese patients with PADAM. Other pathology needs to be addressed for evaluation and diagnosis of PADAM in Japan.
Andropause (male menopause) has received widespread attention in the popular and medical media in the last few years. The International Society for the Study of the Aging Male (ISSAM) coined the acronym PADAM, which stands for partial androgen deficiency of the aging male,1 to designate this condition. It is well known that the serum androgen level declines with age and that this decline is the main cause of PADAM. In plasma, testosterone is bound nonspecifically to albumin and specifically to sex hormone binding globulin (SHBG); a small percentage is available as unbound or free testosterone (FT). FT and testosterone bound nonspecifically to albumin constitute bioavailable testosterone (BT), which reflects the physiological activity of testosterone. Although assay of FT by equilibrium dialysis is the method recommended by ISSAM and others, it is difficult to perform, not automated, and largely inaccessible to most clinicians. The most reliable indicator of PADAM is reported to be BT.1 However, BT measurement is also too complicated, difficult, and expensive to be used routinely in Japan because it is not automated and not covered by the National Health Insurance. Thus, a formula available on the ISSAM website (http://www.issam.ch/freetesto.htm) can be used to calculate BT (cBT) and FT (cFT), which is equivalent to the FT value determined by equilibrium dialysis, from values of total testosterone (TT) and SHBG, and ISSAM recommends using cutoff values to diagnose hypogonadism in PADAM: TT 11 nmol/l; cFT 0.255 nmol/l; cBT 3.8 nmol/l.1, 2 However, even this formula is not generally used in Japan because measurement of serum SHBG is also not covered by the National Health Insurance.
In the present study, we investigated several endocrinologic factors and the degree of symptoms in patients with PADAM and compared them between patients with and without hypogonadism identified on the basis of each of the cutoff values of TT, cFT, and cBT, to confirm whether hypogonadism of patients with PADAM is related to symptoms and clarify which criteria of testosterone recommended by ISSAM is suitable for Japanese patients.
Materials and methods
Our study group comprised 90 men who were over 50 y of age and who visited one of our special clinics for sexual function at Osaka University Hospital or an affiliated hospital between September 2002 and August 2004 with a chief complaint of decreased libido, erectile dysfunction, depression, general fatigue, or any other PADAM symptoms. We excluded patients with an obvious pre-existing condition that could contribute to erectile dysfunction, such as diabetes mellitus, heart disease, renal failure, or a prior surgery in the pelvic cavity. Patients ranged in age from 50 to 79 y (median, 56 y). General symptoms for PADAM were judged according to the aging males symptoms (AMS) scale.3, 4 Erectile function and depressive status were judged according to the International Index of Erectile Function (IIEF-5) and the self-rating depression scale (SDS), respectively. Blood samples were collected between 0900 and 1100 h for monitoring of endocrinologic variables including estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), TT, and prolactin (PRL) levels. TT, E2, and SHBG were measured by radioimmunoassay (RIA), whereas LH, FSH, and PRL were measured by enzyme immunoassay. cFT and cBT were calculated on the basis of TT and SHBG according to the formula shown on the ISSAM website (http://www.issam.ch/freetesto.htm). If hypogonadism was identified on the basis of each of cutoff values of TT, cFT, and cBT, a repeat blood sample was evaluated. When serum concentration of both samples showed lower than cutoff values, the patient was finally diagnosed as hypogonadism. For comparison, all patients were classified as having or not having hypogonadism on the basis of each of the ISSAM cutoff levels for TT, cFT, and cBT. That is, patients with serum TT less than 11 nmol/l (3.17 ng/ml) were considered to have hypogonadism, whereas those with a normal serum TT concentration were not. Likewise, patients with serum cFT less than 0.255 nmol/l (0.0735 ng/ml) were considered to have hypogonadism, whereas those with a normal serum cFT concentration were not; and patients with a serum cBT concentration less than 3.8 nmol/l (1.1 ng/ml) were considered to have hypogonadism, whereas those with a normal serum cBT level were not. Thus, all patients were classified three times. Endocrinologic values and PADAM symptoms were then compared between patients with and without hypogonadism within each of the three groups.
Data are presented as mean±s.d., and statistical analysis was performed by unpaired Student's t-test. A P-value of less than 0.05 was considered statistically significant.
A total of 43 patients (47.8%) had a serum TT concentration less than 3.17 ng/ml, and 47 patients (52.2%) had a normal serum TT concentration (Table 1). The serum cFT and cBT concentrations were significantly lower in patients with a serum TT concentration less than 3.17 ng/ml than in those with a normal TT level. The serum LH level was also significantly lower in patients with a serum TT concentration less than 3.17 ng/ml than in those with a normal TT concentration. Other endocrinologic valuables did not differ significantly. With respect to PADAM symptoms, no significant difference was found in AMS (total and subscales), IIEF-5, or SDS scores.
In all, 55 patients (70.5%) had a serum cFT concentration less than 0.0735 ng/ml, and 23 patients (29.5%) had a normal serum cFT concentration (Table 2). Serum TT and cBT concentrations were significantly lower in patients with a serum cFT concentration less than 0.0735 ng/ml than in those with a normal cFT concentration. No other endocrinologic variables differed significantly. With respect to PADAM symptoms, no significant difference was found in AMS (total and subscales), IIEF-5, or SDS scores.
In all, 14 patients (17.9%) had a serum cBT concentration less than 1.1 ng/ml and 64 patients (82.1%) had a normal serum cBT concentration (Table 3). Serum TT and cFT concentrations were significantly lower in patients with a serum cBT concentration less than 1.1 ng/ml than in those with a normal cBT concentration. No other endocrinologic variables differed significantly. With respect to PADAM symptoms, no significant difference was found in AMS (total and subscales), IIEF-5, or SDS scores.
PADAM is defined by ISSAM as a biochemical syndrome associated with advancing age and is characterized by a deficiency in serum androgen with or without decreased genomic sensitivity to androgen.1 Clinical symptoms of PADAM include fatigue, depression, alterations in mood and cognition, decreased body hair, skin changes, decreased lean body mass with associated diminution in muscle volume and strength, decreased libido, and erectile dysfunction.5, 6, 7, 8 It has been difficult to define deficiency in serum androgen because the criteria by which hypogonadism can be diagnosed for PADAM has been not determined. Only one criterion has been reported by ISSAM1: PADAM may be diagnosed if serum TT, cFT, or cBT concentration is less than 11 nmol/l (3.17 ng/ml), 0.255 nmol/l (0.0735 ng/ml), or 3.8 nmol/l (1.1 ng/ml), respectively.
In the present study, when the cutoff serum TT value was used for a diagnosis of hypogonadism, naturally the serum cFT and cBT concentrations were also significantly lower in patients with hypogonadism than in those without hypogonadism. Likewise, the serum TT and cBT concentrations were significantly lower in patients with hypogonadism than in those without hypogonadism when the cutoff serum cFT value was used and the serum TT and cFT concentrations were significantly lower in patients with hypogonadism than in those without hypogonadism when the cutoff serum cBT value was used. The serum LH level was also lower in patients with hypogonadism than in those without hypogonadism, although a comparison showed a statistical significance only when the cutoff serum TT value was used (Table 1). This decrease of serum LH concentration in patients with hypogonadism was reasonable because a characteristic of endocrinological status in aging male was a dicrease in release of gonadotropin causing andropause (PADAM).9 Testosterone is a hormone responsible for the secondary sex characteristics that appear at puberty. It has a potent effect on stimulating libido, arousal, and erectile function. It is also an anabolic hormone that enhances metabolic processes in muscles, bones, bone marrow, the immune system, and the brain (cognition and mood). Thus, reduced testosterone level can cause sexual, somatovegetative, and psychological symptoms that are called as PADAM symptoms. With regard to psychological symptom, it was reported the Beck Depression Inventory score was significantly and inversely associated with BT.10 It was also reported that lean body mass, total adipose mass, and muscle mass correlated with FT level.11, 12 Furthermore, bone mineral density has been reported to correlate significantly with BT level.13, 14, 15 We previously reported that cBT correlates significantly with age and the IIEF-5 score for erectile function increased significantly with increases in cBT in the study of 130 men having symptoms of sexual dysfunction.16 These previous reports indicate that serum testosterone level must be associated with PADAM symptoms. However, it was reported that none of the scores of the three domains (psychological, somatovegetative, and sexual) of the AMS questionnaire, which is one of most reliable questionnaires for a diagnosis of PADAM and by which PADAM symptoms are generally evaluated, correlated significantly with TT, FT, or BT in a study of 161 healthy, ambulatory, elderly men.17 It was also reported that there was no correlation between the AMS (total and subscales) scores and testosterone levels in the study of 81 self-referred PADAM patients and that an only positive correlation was found between the somatovegetative subscale of the AMS questionnaire and both body mass index and serum insulin level.18 In the present study, the AMS (total and subscales) scores did not differ significantly between patients with and without hypogonadism even when any cutoff values of TT, cFT, and cBT were used. This result suggests that any parameter of testosterone is not closely related to PADAM symptoms. They also indicate that testosterone does not act, at least, directly on arousal and erectile function for PADAM patients. Furthermore, it is still obscure whether ISSAM's criterion can be adopted for Japanese patients with PADAM.
Several indicators of androgen deficiency, such as TT, FT measured by the analog ligand RIA method, cFT, BT, and cBT, have been evaluated and used worldwide for the diagnosis of PADAM. However, PADAM symptoms evaluated by AMS, IIEF-5, or SDS scores are not related to testosterone level. We conclude that other pathology needs to be addressed for evaluation and diagnosis of PADAM in Japan.
Morales A, Lunenfeld B . Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. International Society for the Study of the Aging Male. Aging Male 2002; 5: 74–86.
Vermeulen A, Verdonck L, Kaufman JM . A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 3666–3672.
Heinemann LA et al. A new ‘aging males' symptoms’ (AMS) rating scale. Aging Male 1999; 2: 105–114.
Heinemann LA et al. The Aging Males' Symptoms (AMS) scale: update and compilation of international versions. Health Qual Life Outcomes 2003; 1: 15.
Morley JE . Androgens and aging. Maturitas 2001; 38: 61–71, discussion 71–63.
Morley JE, Perry III HM . Androgen deficiency in aging men. Med Clin North Am 1999; 83: 1279–1289, vii.
Vermeulen A . Andropause. Maturitas 2000; 34: 5–15.
Morales A, Heaton JP, Carson III CC . Andropause: a misnomer for a true clinical entity. J Urol 2000; 163: 705–712.
Lamberts SW, van den Beld AW, van der Lely AJ . The endocrinology of aging. Science 1997; 278: 419–424.
Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D . Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J Clin Endocrinol Metab 1999; 84: 573–577.
Baumgartner RN et al. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999; 107: 123–136.
Abbasi AA et al. Predictors of lean body mass and total adipose mass in community-dwelling elderly men and women. Am J Med Sci 1998; 315: 188–193.
Greendale GA, Edelstein S, Barrett-Connor E . Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. J Bone Miner Res 1997; 12: 1833–1843.
Khosla S, Melton III LJ, Atkinson EJ, O'Fallon WM . Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 2001; 86: 3555–3561.
Khosla S et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 1998; 83: 2266–2274.
Tsujimura A et al. Bioavailable testosterone with age and erectile dysfunction. J Urol 2003; 170: 2345–2347.
T'Sjoen G, Goemaere S, De Meyere M, Kaufman JM . Perception of males' aging symptoms, health and well-being in elderly community-dwelling men is not related to circulating androgen levels. Psychoneuroendocrinology 2004; 29: 201–214.
T'Sjoen G et al. Self-referred patients in an aging male clinic: much more than androgen deficiency alone. Aging Male 2003; 6: 157–165.
We are very grateful to M Omune, M Oki, and S Tanabe of our laboratory for assistance in sample collection and for useful discussions.
About this article
Cite this article
Tsujimura, A., Matsumiya, K., Miyagawa, Y. et al. Comparative study on evaluation methods for serum testosterone level for PADAM diagnosis. Int J Impot Res 17, 259–263 (2005) doi:10.1038/sj.ijir.3901300
- total testosterone
- calculated testosterone
- partial androgen deficiency of the aging male
Association Between Serum Testosterone and Serum PSA Among Men With and Without Partial Androgen Deficiency
Indian Journal of Clinical Biochemistry (2018)
High prevalence of hypogonadism determined by serum free testosterone level in Japanese testicular cancer survivors
International Journal of Urology (2018)
Urologic Clinics of North America (2016)
Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015)
The Journal of Sexual Medicine (2016)
Iranian Red Crescent Medical Journal (2015)