In accordance with improved socioeconomic conditions and advanced medical treatments, the aging of the population has become an issue recently for society overall. Along with a constant increase in the average life span in Korea, the desire for quality of life (QoL) among the elderly population has also increased rapidly compared with that in the past. Aging is accompanied by several age-related symptoms that appear secondary to irreversible and progressive atrophic and degenerative changes as well as intrinsic compositional changes in the body. These symptoms include reductions in happiness, physical capacity, muscle mass, muscle strength, fertility, masculinity, libido, and sexual function. Aging individuals also develop increased body fat, osteoporosis, incontinence, atherosclerosis, cognitive impairment, memory disorders, emotional disturbances, and sleep disorders [1]. In addition, aging may induce changes in endocrinological function, such as that of testosterone. In the Massachusetts Male Aging Study (MMAS), Gray et al. [2] found that total testosterone decreased by 0.4% annually. Furthermore, 7% of 40- to 60-year-old males, 21% of 60- to 80-year-old males, and 35% of >80-year-old males had a total testosterone level under 350 ng/dL, which is below the normal range. Werner [3] defined such endocrinological changes in males as late-onset hypogonadism (LOH), similar to climacteric changes in females. Multiple subsequent studies reported that symptoms such as hot flashes, nervousness, depression, organic brain dysfunction, and reductions in libido and erectile function were associated with decreased testosterone. Unlike climacteric symptoms in females, the decrease in testosterone is neither involved in drastic changes nor is a common phenomenon among all males. Not all aging males are prone to the reduction in testosterone induced by endocrinological dysfunction. In addition, whether the symptoms related to LOH are proportionally associated with the reduction in testosterone remains unclear. Therefore, there are different perspectives on the diagnosis, treatment, management, and follow-up of LOH in males. In fact, the relationship between the symptoms of LOS in aging males and the testosterone level is important for not only the diagnosis of LOH, but also in terms of the theoretical rationale of testosterone replacement therapy for management and evaluation of treatment results. To our knowledge, however, few studies on this topic have been carried out in Korea. Therefore, the objective of this study was to investigate the relationship between the symptoms of LOH and testosterone levels in aging males.

As QoL has improved in recent years, the life span in males has increased and the aging population in Korea has increased. Along with such changes have come drastic changes in the awareness of the health of elderly individuals. In other words, more attention has been paid to the diseases that influence QoL instead of to life-threatening diseases. LOH is one such disease that affects QoL in elderly individuals, who were not of great interest as study subjects in the past owing to their short remaining life span and the small number of available patients.

The most important clinical implication of LOH is that even though it markedly lowers QoL, the disease can be treated easily with simple methods if testosterone replacement therapy is carried out. In particular, the treatment generally includes mild medication and is thus associated with a relatively lower burden for elderly individuals. However, hormone agents should not be abused or misused in any cases, especially hormone replacement for management of nonspecific symptoms. Because severe clinical adverse effects are possible, hormones should be handled carefully. Thus, it is important to diagnose LOH as early as possible to maintain QoL.

It is commonly believed that the symptoms, clinical index, and serum total testosterone level should be thoroughly examined in the diagnosis of LOH. It is especially important to determine if the serum total testosterone level is lowered before any management of symptomatic aging males with LOH. In most cases, the symptoms of LOH in males progress slowly and the manifestations do not change drastically, which is the opposite of female climacteric symptoms. It is necessary to use biochemical diagnostic procedures, such as measurement of the serum total testosterone level, for appropriate diagnosis of LOH be cause the differential diagnosis of naturally derived aging phenomena is difficult. In addition, an understanding of the relationship between serum total testosterone and the symptoms of LOH is essential for the development of a theoretical rationale to carry out testosterone replacement therapy. However, although various questionnaires and diagnostic biochemical methods have been used to measure the symptoms of LOH, the criteria for an obvious diagnosis remain controversial. Two studies evaluated the symptoms of LOH, testosterone levels, and their relationship to hormonal changes in the body. Basar et al. [7] suggested that serum dehydroepiandrosterone sulfate and estradiol (E₂) were associated with the symptoms of LOH by use of the Aging Male Symptoms scale and the IIEF in 348 subjects. By contrast, Christ-Crain et al. [8] reported that serum total testosterone, serum free testosterone, and biologically active testosterone levels were not related to the symptoms of LOH. Lin et al. [9] also found that neither serum free testosterone nor biologically active testosterone levels were associated with the symptoms of LOH as determined by the ADAM questionnaire in 650 subjects; this agrees with the results of the present study. In contrast, Tancredi et al. [10] reported that a positive response rate was significantly higher in men with serum free testosterone levels of <70 ng/dL. Positive answers were associated with specific questions on the ADAM questionnaire, including the first (Did you experience a reduction in libido?), fourth (Did you experience a reduction in height?), seventh (Did you experience a reduction in erectile function?), and tenth (Did you experience a reduction in job performance?) questions. Even though several studies, including the present one, have indicated no relationship between serum testosterone and symptoms of LOH, oral, intramuscular, pellet, patch, and gel products have been developed and are widely utilized. Many studies have shown positive effects of these testosterone replacement therapies, such as increased libido and erectile function, protection against fractures owing to an increase in bone density, increased muscle mass, improved muscle strength and physical capacity, improved body shape, energy regain, and improved happiness and mood [11-13]. In previous studies [14,15], we also demonstrated significant improvements in the symptoms of LOH after percutaneous administration of a testosterone patch and oral testosterone agents. Likewise, a number of studies reported that there is insufficient evidence to conclude that the testosterone level is related to the symptoms of LOH, especially sexual function. However, multiple studies reported improvement in the symptoms of LOH by testosterone replacement therapy in patients with lower testosterone levels. This may be because despite a decrease in androgens and the development of associated symptoms, endocrinological dysfunction, which is the most distinctive phenomenon of aging, is considered to be the most vital clinical manifestation associated with LOH and may be induced by a decrease in hormone secretion, including adrenal hormones such as corticosteroid and growth hormone [16,17]. Therefore, endocrine disorders cannot be explained simply by the reduction in testosterone level in patients with LOH. From a medical treatment perspective, changes in testosterone levels are easily diagnosed. In addition, progress such as the development of various treatments to correct hypotestosteronemia, the disappearance and delay of the symptoms owing to these treatments, and confirmation of the treatment results, including QoL improvement, might have forced clinicians to focus on testosterone replacement therapy only.

In the present study, the ADAM questionnaire created by Morley et al. was used as a screening test for the symptoms of LOH [5]. However, the ADAM questionnaire possesses high sensitivity but relatively low specificity for the diagnosis of LOH, meaning that its utility may be somewhat limited [10,18]. The incidence of LOH according to the ADAM questionnaire in this study was 92.6%; thus, biochemical diagnostic tests, including measurement of the serum testosterone level, should accompany the ADAM questionnaire when used as a screening test. Moreover, another limitation is the determination of the effects of LOH treatments, because the ADAM questionnaire is difficult to quantify. Besides the ADAM questionnaire, the AMS questionnaire by Heinemann et al. [19], and the Pusan National University Hospital QoL scoring system by Park et al. [15] can be used. One study used quantitative version of androgen deficiency in aging males questionnaire, which scores and then quantifies each item on the ADAM questionnaire [10]. In the future, the reliability and validity of the screening tests and the results of testosterone replacement therapy according to the questionnaire responses should be investigated.

In the present study, we showed that the IIEF-5 score tended to be increased with elevated serum total testosterone levels, but no significant correlation was found. This result agrees with the results of Korenman et al. [20], who reported no difference in serum biologically active testosterone levels according to the absence or presence of erectile dysfunction in aging males. The MMAS [21] also agreed with our results, suggesting that the free testosterone level, biologically active testosterone level, and total testosterone level are not related to erectile dysfunction. Similar to the studies that reported recovery of sexual functions, such as libido and erectile function, after testosterone replacement therapy [22,23], most patients with LOH who visit urological clinics consider sexual function to be the most important issue, and testosterone replacement therapy is the major practical treatment of LOH. Thus, further studies are required.

There were some limitations to this study. Because we used only the ADAM questionnaire and IIEF-5 to assess the symptoms of LOH through an andropause screening program, the detailed medical and social history of the patients for a full analysis of LOH symptoms were lacking. In addition, serum total testosterone was the only biochemical parameter measured; various endocrinological changes influencing the symptoms of LOH were not included in the study. Although there is consensus that patients with serum total testosterone levels below 230 ng/dL will usually benefit from testosterone replacement therapy according to the ISSAM guideline [18], we used the cutoff value of 350 ng/dL. This was for focused evaluation of the relationship between serum total testosterone and LOH symptoms in patients with serum testosterone levels between 230 to 350 ng/dL, who constitute a large portion of those with LOH. Also, debate remains about the effect of testosterone treatment in these patients. Furthermore, this study may have had some bias, because it was a community-based study, not a cross-sectional or cohort study. However, our findings are important because this is the first large-scale study of Korezan males aged >40 years.

Among men over 40 years of age, 25.6% met the clinical and biochemical diagnostic criteria for LOH. There was no relationship between serum testosterone levels and symptoms of LOH.