Late-onset hypogonadism: current methods of clinical diagnosis and treatment in Japan

Abstract

Testosterone affects several organs in the body and is very important for male well-being. Aging men with late-onset hypogonadism (LOH) experience physiologic, psychiatric, and sexual symptoms related to a decline in the serum concentration of testosterone with age. However, it is well-known that the extent of the decline in testosterone concentration does not correlate with the severity of LOH-related symptoms. Therefore, it is difficult to diagnose and treat patients with LOH. In addition, the symptoms, response to testosterone replacement therapy (TRT), and medical insurance coverage differ among ethnicities and countries. The evaluation of testosterone is essential for the diagnosis and treatment of LOH. The effects of testosterone are determined not only by the serum testosterone concentration but also by the androgen receptor sensitivity. A low number of glutamine repeats is indicative of high androgenic activity, and the number shows ethnicity-related differences (fewer in African American than in Caucasian people and more in East Asian people). The diagnosis of LOH is typically made using subjective symptoms and the serum testosterone concentration. The Aging Male Symptoms scale is widely used to evaluate the symptoms. The normal range of total testosterone concentration varies around the world; therefore, clinicians should follow the guidelines of their regional academic society. The principal treatment for LOH is TRT. There are many types of TRT and other treatment strategies are also available. Thus, physicians should treat LOH according to each patient’s situation, considering related disorders, such as diabetes, osteoporosis, metabolic syndrome, and depression.

INTRODUCTION

It is clear that testosterone is indispensable for male well-being. The serum concentration of testosterone decreases with age in men, and this can be accompanied by several symptoms of late-onset hypogonadism (LOH). These can impair the individual activities of daily living of middle-aged men and have societal effects. Furthermore, systemic comorbidities, such as metabolic syndrome, depression, and frailty, are common in aged men with symptoms of LOH.

In this review, the (1) effects of testosterone in the organs of humans, (2) forms of circulating testosterone and their normal concentration ranges, (3) diagnosis of LOH, (4) treatment strategies for LOH, (5) treatment of disorders associated with LOH, and (6) future challenges are discussed.

EFFECTS OF TESTOSTERONE IN THE ORGANS OF HUMANS

Androgens are principally produced by Leydig cells in the testes and adrenal glands. Testosterone is the most important androgen, is produced in the testes, and has many effects, such as stimulating the development of male genital organs and secondary sexual characteristics, spermatogenesis, and muscle growth.

The physiologic effects of testosterone are mediated through binding to androgen receptors (ARs) or direct effects on cell proliferation. It is thought that testosterone has effects on male genital organs and the central nerve system through ARs, whereas it affects muscle, bone, bone marrow, and skin through its cytosolic effects.1

ARs are widely expressed, including in the brain, vocal cords, skin, testis, bone marrow, male external and internal genitalia, and muscle.2,3 They mediate the effects of testosterone to induce a good mood, voice change in adolescence, spermatogenesis, and erythrocyte synthesis. They also maintain youthful skin, urinary and sexual function, and muscle strength. In addition, when converted to estrogen by aromatase, it is responsible for maintaining a healthy skeleton.2 Thus, it is clear that testosterone is a very important hormone, particularly in men.

The gene encoding the AR is located at the q11–12 site of the X chromosome and consists of eight exons. It generates a 2.8-kb-long mRNA sequence, encoding a protein of approximately 910–920 amino acids. The N-terminal region (encoded by exon A) of this is composed of approximately 560 amino acids, is characterized by repeated glutamine (Gln), proline (Pro), and glycine (Gly) residues, and is principally involved in transcriptional regulation. The CAG base sequence (cytosine, adenine, and guanine) encodes Gln, and importantly, it has recently been reported that the fewer the number of Gln (CAG) repeats there are, the higher the androgenic activity of the protein is.4,5 There are ethnic differences in the number of CAG repeats: the lowest number is present in African–American people, followed by Caucasian people, and a larger number is present in East Asian people. Furthermore, these statistics correspond to the incidences of prostate cancer and related mortality.6,7 These data also imply that Asian men are more resistant to androgens. A recent study showed that the number of CAG repeats significantly correlates with the testosterone concentration of Japanese men, which might suggest that they secrete testosterone to compensate for androgen resistance.8 In addition, testosterone replacement therapy (TRT) was found to be less efficacious in patients with LOH who had the long sequences of CAG repeats. These data imply that the interpretation of testosterone concentration is not simple, and therefore, that further basic and clinical research into LOH is required.

FORMS OF CIRCULATING TESTOSTERONE AND THEIR NORMAL CONCENTRATION RANGES

The most important hormone associated with LOH is testosterone. The total testosterone (TT) concentration is contributed to free testosterone (FT; approximately 2%), testosterone bound to albumin (53%–55%), and testosterone bound to sex hormone-binding globulin (SHBG; 43%–45%). FT and albumin-bound testosterone are considered to be bioavailable, whereas SHBG-bound testosterone is believed to be inactive in the target organs of testosterone. However, a recent study has shown that SHBG-bound testosterone may be bioactive when it is taken up by cells and/or binds to receptors on cell membranes.9 Therefore, further research into the bioactivity of testosterone in men is merited.

The selection of the most appropriate laboratory tests for LOH is an important issue. Data obtained for Japanese men imply that the serum TT concentration does not change with age, and the normal range of TT in Japanese men has established as 2.01–7.50 ng ml⁻¹. Whereas the FT concentration declines with age in Japanese men, and the value of young adult (20–39 years) mean (YAM) ± 2× standard deviation (s.d.) is considered to be the normal range.3,10 The value of 80% and 70% of YAM in Japanese men was concretely 12.4 pg ml⁻¹ and 10.9 pg ml⁻¹, respectively.3,10

Importantly, the FT and bioavailable testosterone concentrations significantly correlate.11 Therefore, the FT concentration could be used for the diagnosis of LOH. However, immunoassays for the measurement of FT concentration have very low reproducibility; therefore, the measurement of FT concentration is not recommended for use in the diagnosis and management of LOH in most countries.

TT is widely used for the diagnosis of LOH, although the cut-off value for TT insufficiency varies among the sets of guidelines.12 Table 1 shows the cut-off values of the concentrations of TT that are recommended by academic associations and societies around the world, including the Internal Society for Sexual Medicine (2015),13 American Urological Association (2018),14 British Society for Sexual Medicine (2017),15,16 Canadian Medical Association Journal (2015),17 Endocrine Society (2018),18 European Association of Urology (2018),19 and Japanese Urological Association (2022).20,21

Table 1.

Biochemical cut-off levels for low total testosterone in guidelines

Guideline	Biochemical cut-off for low TT (ng dl−1)
ISSM (2015)	<231
AUA (2018)	<300
BSSM (2017)	<231
CMAJ (2015)	Not determined
ES (2018)	<264
EAU (2018)	<231
JUA (2022)	<250

Criteria of cut-off levels for low TT in each guideline were cited from Horie and Ide.20 ISSM: Internal Society for Sexual Medicine; AUA: American Urological Association; BSSM: British Society for Sexual Medicine; CMAJ: Canadian Medical Association Journal; ES: Endocrine Society; EAU: European Association of Urology; JUA: Japanese Urological Association; TT: total testosterone

Adequate testosterone concentrations are not defined uniformly around the world, and these may depend on both genetic and cultural factors, including ethnicity and lifestyle. Therefore, clinicians who manage patients with symptoms of LOH should use the most appropriate defined range of testosterone concentrations for each region. And it is important to obtain clinical data regarding the relationships between testosterone concentration and the symptoms of LOH before and after TRT.

DIAGNOSIS OF LOH

LOH is 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.”22 The decline in serum testosterone concentration with age can induce various symptoms, including physiologic, psychiatric, and sexual symptoms, all of which should be evaluated. The Aging Male Symptoms (AMS) scale23 is calculated from responses to a questionnaire and is widely used to evaluate each of these types of symptoms. Seventeen questions are used to calculate the AMS score, consisting of seven related to physiologic factors (questions 1–5, 9, and 10), five related to psychiatric factors (questions 6–8, 11, and 13), and five related to sexual factors (questions 12 and 14–17). The patients grade the severity of each symptom (absent: 1; mild: 2; moderate: 3; severe: 4; and very severe: 5) in response to each question, and the total score is then calculated. The symptoms of LOH are defined as none with a total score of 17–26, mild with 27–36, moderate with 37–49, and severe with ≥50.

As well as an evaluation of the symptoms of LOH, the measurement of serum testosterone concentration is essential to make a diagnosis. It is well known that the circadian rhythm of testosterone concentration (highest in the early morning and decreasing in the afternoon). This circadian rhythm becomes less marked with age.24 Accordingly, it is recommended to measure serum testosterone concentration in the morning.

Because the diagnostic and therapeutic ranges stated in the various guidelines differ,12 clinicians are recommended to treat their patients with LOH according to the regional recommendations. In this review, the Japanese guidelines for hypogonadism and symptoms of LOH in men which were published in 202220 and 202321 are referenced. As mentioned above, FT has been used to evaluate the serum testosterone level, because a decline in FT concentration with age has been demonstrated in Japanese men, using a previous version of the Japanese guidelines.3,10 However, there are several issues associated with the adoption of FT, including the lack of repeatability of the radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) assays. Therefore, TT is generally measured worldwide. In the new Japanese guidelines for LOH, TT is recommended to be used for the diagnosis and treatment of LOH.20,21

The diagnostic and treatment strategies recommended in the new Japanese guidelines for LOH are as follows. In the presence of symptoms of LOH and a serum TT concentration <250 ng dl⁻¹, a diagnosis of LOH is made. For patients with symptoms of LOH and a TT concentration >250 ng dl⁻¹, FT should also be measured, and LOH should be diagnosed when the FT concentration is <7.5 pg ml⁻¹. Furthermore, physicians should also consider treating the symptoms of LOH in patients that do not have low TT or FT concentrations (Figure 1). This new approach has been adopted in view of the fact that Asian men, including Japanese men, have a high level of resistance to androgens.

Figure 1.

Treatment policy for late-onset hypogonadism syndrome described in the new Japanese guidelines (2022).20 LOH: late-onset hypogonadism.

TREATMENT STRATEGY FOR LOH

There are three types of treatment for LOH. The principal treatment is TRT, which replaces the testosterone that is lost during aging. In addition, there are several candidate hormonal and nonhormonal medications for LOH. Symptomatic treatments for LOH are also used in clinical practice.

TRT

There are several types of TRT, including intramuscular injection, transdermal ointments/gels/patches, oral forms, and nasally administered agents. The duration of activity of each form of testosterone-associated medication varies and determines the interval of administration. As shown in Table 2, several types of TRT are available worldwide, but the available type of medication varies regionally.3,25

Table 2.

Examples of testosterone agents

Administration route	Generic name	Product name	Dose
Oral	Fluoxymesterone	Halotestin	2–5 mg daily
	Methyltestosterone	Enarmon	20–50 mg daily
	Testosterone undecanate	Andriol	120–240 mg daily
Intramusclar	Testosterone enanthate	Enarmon depot	125–250 mg every 2–4 weeks
	Testosterone undecanate	Nebido	1000 mg every 12 weeks
	hCG	Gonatropin	3000–5000 units every 3–4 weeks
Ointment or gel	Testosterone patch	Androderm	2.5–5 mg daily
	Testosterone gel	Testim (1%)	50–100 mg daily
	Testosterone gel	AndroGel (1%)	5–10 g daily
	Testosterone gel	TESTOGEL	5 g (50 mg testosterone) daily
	Testosterone ointment	Glowmin	6 mg testosterone daily
	Testosterone gel	1 up formula	5% testosterone (New Japanese gel)
	Testosterone gel	2% novel testosterone gel	2% testosterone (New Japanese gel)
Buccal	Testosterone buccal	Striant	1 tablet (30 mg) twice a day
Nasal	Testosterone nasal gel	Natesto	Total 22 mg or 33 mg, 2–3 times daily

hCG: human chorionic gonadotropin

Unfortunately, only a few types of TRT are available in Japan. The absorption of methyltestosterone in the small intestine is poor and hepatic side effects are common; therefore, this is no longer used. Furthermore, the administration of neither oral testosterone undecanoate (Andriol; Merk Canada Inc., Kirkland, Canada) nor long-acting intramuscular undecanoate (Nebido; Bayer Schering Pharma, Berlin, Germany) is permitted in clinical practice in Japan; and the newly developed nasal short-acting medications26 are not available at present. Accordingly, the intramuscular injection of testosterone enanthate (Enarmon depot; ASKA Pharmaceutical Co., Ltd., Tokyo, Japan) is widely used for the treatment of LOH in Japan. In addition, testosterone ointment (Glowmin; Daito Pharmaceutical Co., Ltd., Tokyo, Japan)27 is used because it is an over-the-counter product that has been approved for the treatment of LOH by the Japanese Ministry of Public Health.

It is well known that there is a circadian rhythm in the testosterone concentrations of men: they peak early in the morning and subsequently decrease.24 The serum testosterone concentration after Enarmon Depot Injection peaks in 1–3 days at a level that is much higher than the normal range, then decreases over the following 2–4 weeks to a level below the original concentration.25 In contrast, the serum testosterone concentration increases to close to the normal range after the administration of the short-acting ointment Glowmin.28 Although the implications of the testosterone circadian rhythm are not clear, the efficacy and safety of short-acting testosterone ointment are good when it is applied according to the circadian rhythm of testosterone.28,29

Several other novel short-acting testosterone-like agents are available in some countries, and there have been some previous comparisons between the short- and long-acting medications.25 No significant difference in the efficacies of long-acting intramuscular injections and short-acting ointments for the treatment of LOH has been reported.30 However, short-acting testosterone treatments seem to be associated with fewer adverse reactions than long-acting preparations. Furthermore, the reductions in the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations are smaller following the administration of short-acting testosterone.30,31 Short-acting testosterone preparations have also been reported to have a smaller effect on male reproductive potential than the long-acting equivalent.32,33 Finally, polycythemia has been shown to be more severe when long-acting testosterone preparations are administered than short-acting preparations.34,35 Thus, the appropriate testosterone formulation to use for the treatment of patients with LOH is another important subject for future research.

The identification of good candidates for the treatment of LOH using each testosterone formulation is another important challenge. A known predictor of the efficacy of TRT for LOH is the testosterone/estradiol (T/E2) ratio;36 a low T/E2 ratio predicts a poor response to TRT. It is important to evaluate the potential efficacy of TRT before it is commenced, and therefore, future research should aim to identify the additional predictors of TRT.

It is essential to know the contraindications and potential adverse effects of TRT. At present, the relationship between TRT and cardiovascular events is controversial. According to the results of a previous meta-analysis, the risk of cardiovascular events is not increased by TRT. However, a few studies have generated contradictory results, indicating a higher risk within 1 year of TRT and in older patients (>65 years).37 Therefore, it is necessary to perform TRT with caution, especially in patients who have undergone TRT <1 year previously and in older men.

Polycythemia is commonly identified following TRT. Therefore, during TRT, blood sampling is essential, and TRT should be discontinued when polycythemia is identified. Because polycythemia is typically identified 3–6 months after the initiation of treatment, blood sampling should be performed soon after the commencement of TRT. In addition, it is recommended to check polycythemia every 3 months.20,21 TRT has also been reported to worsen sleep apnea syndrome (SAS).38 Therefore, it should be performed in SAS patients alongside the maintenance of continuous positive airway pressure. Furthermore, the suppression of gonadotropin secretion is induced by TRT, which results in the inhibition of spermatogenesis. In general, LOH patients are middle-aged or older; therefore, most are not concerned about their fertility. However, physicians should check whether a patient wishes to have children before starting TRT.

Oral TRT can induce liver dysfunction, because these medications are absorbed from the small intestine and reach the liver directly through the portal vein. However, although intramuscular and transdermal TRT rarely affect liver function, it should be assessed regularly.

Finally, prostate cancer is one of the most important considerations with respect to the use of TRT. Previous studies have shown that a low serum testosterone concentration might be associated with malignant prostate cancer,39,40 but there is no clear evidence of a link between serum testosterone concentration and the detection of prostate cancer.41,42 Indeed, several studies have shown that TRT does not increase the risk of prostate cancer.43,44,45,46 However, the prostate should be evaluated, including by measuring the prostate-specific antigen (PSA), before commencing, and during TRT. To ensure the safety of patients, TRT should be avoided for LOH patients with a PSA concentration >2.0 ng ml⁻¹.3

An alternative hormonal therapy

In addition to TRT, human chorionic gonadotropin (hCG), which has LH-like effects, may be a candidate for LOH therapy when the testicular function of patients is preserved.47 Clomiphene citrate is a selective estrogen receptor modulator (SERM) that causes the release of LH and FSH from the pituitary gland, which is followed by an increase in testosterone secretion. Clomiphene is typically administered to improve sperm quality. Although there have only been a few reports of the amelioration of LOH-related symptoms by clomifene,48,49 we have found that clomiphene is an effective means of relieving the symptoms of LOH in middle-aged men with infertility.

Alternative treatments for LOH

In East Asian countries, such as China, Korea, and Japan, traditional herbal medicine is used for the treatment of numerous diseases. One of the disorders that is typically treated using traditional herbal medicine is menopausal syndrome.50 Both LOH and female menopausal disorders are the result of an age-related decline in sex hormone levels. Therefore, traditional medicinal products might also be expected to be efficacious for men with LOH, and indeed, several studies have shown that certain products are safe and efficacious means of treating LOH.51,52,53,54

In Western medicine, physicians identify and exclude the causes for diseases, whereas the goal of traditional herbal medicine is to maintain the status of patients (SHO; in Japanese, SHO means patient’s general condition, such as tough, intermediate, or weak)54 in the midrange, with no excess or insufficiency of substances that might be related to pathology. Thus, traditional herbal medicine is not used according to the cause of a disease but rather aims to correct pathologies by selecting suitable treatments for each individual. It is challenging to choose the most suitable medicine for a patient according to SHO; therefore, an excess/insufficiency scoring system, based on the answers to a questionnaire, is typically used to make decisions regarding the patient’s SHO.54 The efficacy and safety of traditional herbal medicine are widely accepted in East Asia, and it has been shown that with the careful selection of traditional Japanese herbal products, the efficacy of this approach is approximately 70%, with few side effects being reported.54 Therefore, we use Japanese herbal medicine for the treatment of LOH patients, especially when TRT is contraindicated. The components of the principal Japanese herbal medicines that are used for LOH are listed in Box 1, and the types of patients and conditions that are associated with the successful use of such medications are shown in Table 3.

Box 1.

Components of Japanese herbal medicine for late-onset hypogonadism.

Table 3.

Choice of Japanese herbal medicine for late-onset hypogonadism

Japanese herbal medicine	Pathogenic alteration “SHO” (excess–insufficiency)	Indications of patient’s conditions
Keishibukuryogan	Excess	Strong build, ruddy face, substantial abdomen, and lower abdominal defiance
Kamishoyosan	Intermediate	Infirm, shoulder stiffness, fatigue, and anxiety
Saikokeishikankyoto	Intermediate–insufficiency	Loss of physical strength, sensitivity to cold, palpitation, and nervous
Tokishakuyakusan	Insufficiency	Weak muscle, fatigue, and sensitive to cold (lumber–lower extremities)
Hachimijiogan	Insufficiency	Severe fatigue, urinary frequency, and ED
Hochuekkito	Insufficiency	Lower digestive function, severe lower extremities fatigue, and infirm
Saikokaryukotsuboreito	Excess–intermediate	Good–fair physical strength, palpitation, sleep disturbance, and irritated
Yokukansan	Insufficiency	Frail condition, neurosis, and sleeplessness

SHO: in Japanese, it means patient’s general condition, such as tough, intermediate, or weak; ED: erectile dysfunction

Summary of the treatment strategies for the three principal symptoms of LOH

The principal physiologic symptom of LOH is muscle weakness, which is a good indication for TRT, because testosterone is an anabolic steroid that increases muscle volume. Recently, frailty and sarcopenia have been shown to have serious adverse effects on the longevity and quality of life of older people, and these conditions frequently require management in clinics for patients with LOH.1,20

Approximately 40% of patients attending an LOH clinic were shown to have previously undergone psychological consultations.55 Therefore, the management of mental health issues is important in LOH clinics. The psychiatric symptoms of patients with LOH, including depression, can be treated using selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) alongside their specific therapy for LOH. TRT is also an effective means of improving mental health, and therefore, combination therapy of TRT and psychiatric medications may be appropriate. However, when a patient’s symptoms are severe, a psychiatrist should be involved in their treatment.

One of the most important types of sexual dysfunction encountered is erectile dysfunction (ED), and phosphodiesterase-5 (PDE-5) inhibitor is the first-choice treatment for this condition. Thus, in addition to TRT, these treatments may also have to be administered, depending on the symptoms of individuals with LOH.

TREATMENT OF DISORDERS ASSOCIATED WITH LOH

Receptors for testosterone are expressed in many organs, implying that various signs and symptoms can be associated with LOH and that TRT may relieve all of these.

Diabetes mellitus (DM)

Low serum TT concentrations of <10 nmol l⁻¹ (288 ng dl⁻¹) are present in many patients with type 2 DM,56 and the fasting glucose concentrations of patients can be improved by the administration of long-acting intramuscular undecanoate (Nebido; Bayer Schering Pharma, Berlin, Germany) for up to 60 months.57 Thus, TRT may be beneficial for patients with DM.

Osteoporosis

Low serum testosterone concentrations have been reported to be associated with low bone mineral density, and TRT has been shown to increase bone mineral density, especially in patients with low testosterone concentrations.58 Although the first-choice medications for osteoporosis are bisphosphonates and denosumab,59,60 TRT may represent a useful additional treatment for patients with osteoporosis.

Metabolic syndrome

Patients with LOH often also have metabolic syndrome and obesity. Lipoprotein lipase (LPL) on adipocyte membranes breaks down serum triglyceride for storage in these cells, but testosterone inhibits LPL. Therefore, adipocytes undergo hypertrophy in the presence of low testosterone concentrations.61 Furthermore, TRT has direct effects on adipocytes, maintains muscle volume, and thereby aids physical exercise. Thus, TRT may also ameliorate metabolic syndrome.62

Depression

Many patients that attend clinics for LOH also undergo treatment at psychiatric clinics at the same time.55 Psychological symptoms in LOH are similar to other psychiatric diseases. In addition, psychologic stress reduces the circulating testosterone concentration. Thus, it is impossible to reliably distinguish patients with LOH from those with other psychiatric diseases based on only their symptoms and/or serum testosterone levels. In general, SSRIs and SNRIs are used for the treatment of depression, but TRT also has effects on the central nervous system, increasing libido, aggression, and motivation. Therefore, TRT may have favorable effects on a patient’s mental state. However, the involvement of psychiatrists in the management of patients with serious symptoms, such as suicidal thoughts, is essential.

Frailty and sarcopenia

There is a documented relationship between hypogonadism and frailty/sarcopenia in older men, and the maintenance of an appropriate testosterone concentration is important for the prevention of frailty.63 Furthermore, the use of TRT for LOH significantly increases leg muscle volume,64 which counteracts sarcopenia. Herbal medicines, such as Hochuekkito, Juzentaihoto, and Ninjin’yoeito,65 are sometimes used for the treatment of frailty in Japan, and Hochuekkito is a promising candidate treatment for LOH. Thus, treatments for LOH may also help prevent and/or treat frailty and sarcopenia.

Sexual dysfunction

Sexual dysfunction is one of the principal components of LOH, and ED is the most commonly related symptom. The most effective treatments for ED are PDE-5 inhibitors, which induce the relaxation of blood vessels through effects on endothelial cells. This effect occurs in penile blood vessels but is also apparent throughout the body. Daily tadalafil administration has been reported to improve endothelial function in patients with benign prostatic hyperplasia,66 and PDE-5 inhibitors may also have beneficial effects in blood vessels affected by arteriosclerosis.

The potential direct relationship between ED and testosterone concentration is controversial. Three symptoms of male sexual dysfunction (low ability/frequency of sexual activity, low frequency of morning erections, and low libido) have been shown to be related to the TT and FT concentrations of Han Chinese people.67 Furthermore, TRT has been shown to improve the International Index of Erectile Function (IIEF) scores of hypogonadal men without affecting their voiding parameters or PSA concentrations.68 However, TRT has also been shown to have little or no effect on erectile function in the short or long term.69 Although a low testosterone concentration is not the main cause of ED, it does affect this disorder. Furthermore, TRT would be expected to increase libido and to increase the efficacy of PDE-5 inhibitors when used for the treatment of ED in patients with hypogonadism.70,71

FUTURE CHALLENGES

LOH patients typically have numerous symptoms, and it is often difficult to distinguish patients with LOH from those with other disorders. Some of these patients will have visited several medical departments for the treatment of various conditions. Therefore, the promulgation of information regarding the clinical concept of LOH among medical professionals is essential.

For the accurate diagnosis for LOH, appropriate evaluation of serum testosterone concentrations is critical. TT is widely used in the diagnosis of LOH, but the normal ranges for TT stated in the various guidelines differ somewhat. It is impossible to define a single range for the use in the diagnosis of LOH because testosterone sensitivity/resistance varies between people of differing ethnicity. Therefore, the most appropriate testosterone concentrations should be determined on the basis of the clinical and research data regarding patients in each region.

The treatment strategy of LOH also represents a key issue to address in future. TRT is a promising treatment for LOH, and there are several available drug formulations, the choice of which depends on the institution. Thus, the first step is to determine which TRT medications are available and would be the most suitable in the region. Subsequently, the most suitable formulation should be used to ameliorate the symptoms of LOH that are present in each patient. Physicians in each region should adopt the same concepts regarding the treatment of LOH. To resolve these issues, further basic and clinical studies are required.

CONCLUSION

LOH develops because of a decline in serum testosterone concentration with age. Testosterone receptors are expressed in a number of organs in the male body, meaning that various signs and symptoms can develop, including physical, psychiatric, and sexual symptoms.

Diagnoses of LOH are made principally by evaluating the symptoms and the serum testosterone concentrations of the patients. The AMS scale is widely used to characterize the symptoms of LOH in men. Because a standard normal range for TT concentration has not been established worldwide, clinicians should evaluate such patients according to the guidelines of the regional academic societies.

The principal treatment for LOH is TRT. There are many types of TRT and other treatment strategies are also available. Thus, physicians should treat LOH with reference to each patient’s situation. In particular, because testosterone has effects in many organs, the treatment of LOH using TRT may also relieve comorbidities in older men.

Finally, it is our duty to address the various remaining challenges in the diagnosis and management of patients with LOH.

COMPETING INTERESTS

The author declares no competing interests.