STATE-OF-THE-ART REVIEW IN ENDOCRINOLOGY
The impact of testosterone in men’s health
2023 Volume 70 Issue 7 Pages 655-662
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2023 Volume 70 Issue 7 Pages 655-662
Testosterone plays a key role in the maintenance of physical and mental functions in men. Age-related testosterone decline is closely associated with sarcopenia and muscle deterioration, while testosterone decline is linked with the etiology and prevention of diseases such as angina pectoris, arteriosclerosis, obesity, metabolic syndrome, and dementia. Late-onset hypogonadism (LOH) is defined as a disease characterized by age-related testosterone decline and associated clinical symptoms. Testosterone replacement therapy improves health-related QOL in patients with LOH.
Testosterone declines with age. LOH (late-onset hypogonadism), occurring in men with declining testosterone, is not equivalent to the major event of menopause, which women experience as a range of symptoms [1]. Testosterone decrease is gradual, and its degree and the timing of related symptoms are highly individual. When the elderly develop chronic illnesses, frailty progresses and QOL decreases due to cognitive decline, and lessened motor and sexual function [2]. A relationship between these pathologies and low testosterone has been suggested. While healthy aging has become an important social and medical issue, a medical approach is needed to determine how physical and mental health can be maintained and evaluated. In our progressively aging society, testosterone may become a key indicator of male health maintenance.
Androgens include testis-derived testosterone and dihydrotestosterone (DHT), as well as adrenal gland-derived dehydroepiandrosterone (DHEA) and DHEA-S (DHEA-sulfate). 11-ketotestosterone (11-KT) is another class of active androgen that can be converted from testosterone. 11-KT is produced in the testicular Leydig cells and is one of the major classes of androgens found in human [3]. Testosterone secretion is mediated by the gonadotrophin-releasing hormone (LH-RH or Gn-RH) synthesized in the hypothalamus, stimulating the anterior pituitary gland to secrete the gonadotrophins LH (luteinizing hormone) and FSH (follicle-stimulating hormone). LH stimulates Leydig cells in the testis and promotes testosterone production [4] (Fig. 1). FSH and testosterone act on the Sertoli cells in the seminiferous tubules to promote the maintenance of spermatogenic function. Approximately 98% of testosterone in the blood is bound to sex hormone-binding globulin (SHBG) or albumin, with the remaining 1–2% existing as free testosterone. Total testosterone is a combination of both the bound form (i.e., testosterone bound to SHBG or albumin) and the free form [5]. Bioavailable testosterone is a combination of free testosterone and albumin-bound testosterone, with the latter believed to separate relatively easily to exhibit its physiological activity [6].
Synthesis and secretion of testosterone. GnRH: gonadotropin-releasing hormone, LH: luteinizing hormone, FSH: follicle-stimulating hormone, DHEA: dehydroepiandrosterone, DHT: dihydrotestosterone, SHBG: sex hormone binding globulin
Testosterone acts by being converted to highly active DHT by the action of 5α-reductase in the target tissue. DHEA is similarly believed to convert to, and act as, testosterone and DHT. The androgen receptor (AR), the receptor for testosterone and DHT, is a nuclear receptor which, when bound to testosterone or DHT, acts as a transcription factor for target genes and exhibits biological activities [7]. Androgen receptors are widely distributed in the reproductive organs as well as in the brain, blood vessels, and peripheral nerves.
The effects of testosterone and its metabolites are both widespread and indispensable in the development of secondary sex characteristics in puberty. Testosterone promotes sexual desire and is involved in muscle development, voice change, the development of body hair, and spermatogenesis. In adults, testosterone is necessary for maintaining muscle mass and strength, and is believed to be involved in visceral fat reduction, hematopoiesis, and cognitive function [8]. Decreased testosterone levels can lead to lowered insulin sensitivity and induce metabolic syndrome. They can also impact sexual and cognitive function, generate mood disorders, increase visceral fat, reduce muscle mass, generate anemia, and decrease bone density, significantly decreasing men’s QOL [9]. In the early stage of puberty, the hypothalamus secretes GnRH, which activates testosterone production through increased secretion of LH and FSH in the pituitary gland. It has been reported that kisspeptin peptide and GPR54 receptor play a key role in GnRH secretion during puberty, based on knockout mouse analysis [10]. Testosterone continues to rise until about age 20, declining gradually thereafter.
Testicular volume is about 31% less in men over age 75 compared with men aged 18 to 40 [11]. Histomorphological studies show an age-related decrease in the number of seminiferous tubules, as well as a decrease in the number of embryonic and Sertoli cells. Semen volume, total sperm count, sperm motility, and normal morphology sperm ratio have been shown to decrease after age 35 or thereabouts.
Age-related decreases in the number of Leydig cells producing testosterone in the testis, the responsiveness of Leydig cells to LH, and the amount of secreted GnRH, leads to a testosterone decline. Some 2–5% of 40-year-olds, and 30–70% of 70-year-olds, are believed to have decreased testosterone levels [12].
Iwamoto et al.’s study in Japanese males showed little age-related decrease in total testosterone levels and almost no change after age 50. Free testosterone levels, on the other hand, decreased with age [13]. Age-related changes in BMI, total testosterone, free testosterone, LH, and SHBG have been reported in 3,220 men over age 40 [14]. Obesity is a known cause of hypogonadism, and both total and free testosterone were lowest in the group with a BMI of at least 30 kg/m2 compared to the groups with a BMI of 25 kg/m2 and 25 to 30 kg/m2, respectively. Moreover, age-related changes are more evident in SHBG increases as well as in decreasing free testosterone due to aging. In the European Male Ageing Study, testosterone was analyzed in men aged 40–79. Mean (±S.D.) annualised hormone changes were as follows: testosterone –0.1 ± 0.95 nmol/L; free testosterone –3.83 ± 16.8 pmol/L and SHBG 0.56 ± 2.5 nmol/L. Beyond 50 years of age, there was a greater decrease in testosterone and free testosterone [15].
The condition caused by an age-related decrease in testosterone is defined as LOH. Symptoms of LOH include general fatigue, decreased libido, decreased motivation, ED, decreased concentration, insomnia, irritability, stiff shoulders, urinary problems, heavy headedness, tinnitus, and decreased early-morning erections. Moreover, in aging men, decreased testosterone is associated with depression, hypogonadism, cognitive decline, osteoporosis, cardiovascular disease, increased visceral fat, lessened insulin sensitivity, decreased high-density lipoprotein cholesterol (HDL), and increased total cholesterol levels and low-density lipoprotein cholesterol (LDL) [2]. Conversely, diseases underlying LOH syndrome such as metabolic syndrome, arteriosclerosis, diabetes, hypertension, and hyperlipidemia must be considered. Insulin resistance and obesity are associated with decreased testosterone levels.
The Aging Males’ Symptoms (AMS) scale (Table 1) is the primary international symptom score for LOH. The AMS scale is a self-rated symptom score of 17 items including mental/psychological, physical, and sexual, functions. The 17 items are scored using a 5-point evaluation. Total scores of 26 or fewer points indicate normal, 27–36 suggest mild symptoms, 37–49 express moderate symptoms, and 50 or more points signal severe symptoms. AMS is utilized not only for diagnosis, but also as a marker evaluating the efficacy of testosterone replacement therapy (TRT) [16]. The AMS scale has been broadly utilized in screening [16-18], but it is characterized by high sensitivity and low specificity, with European Association of Urology guidelines strongly recommending against usage of the questionnaire in systematic screening [19].
| Symptom | None | Mild | Moderate | Severe | Extreme | |
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| 1 | Decline in your feeling of general well being | |||||
| 2 | Joint pain and muscle ache | |||||
| 3 | Excessive sweating | |||||
| 4 | Sleep problems | |||||
| 5 | Increased need for sleep, often feeling tired | |||||
| 6 | Irritability | |||||
| 7 | Nervousness | |||||
| 8 | Anxiety | |||||
| 9 | Physical exhaustion/lacking vitality | |||||
| 10 | Decrease in muscular strength | |||||
| 11 | Depressive mood | |||||
| 12 | Feeling that you have passed your peak | |||||
| 13 | Feeling burnt out, having hit rock-bottom | |||||
| 14 | Decrease in beard growth | |||||
| 15 | Decrease in the number of morning erections | |||||
| 16 | Decrease in ability/frequency to perform sexually | |||||
| 17 | Decrease in sexual desire/libido |
Score 17–26: None, 27–36: Mild, 37–49: Moderate, over 50: Severe
In the European Male Ageing Study, loss of early-morning erections, decreased libido, and erectile dysfunction were associated with low serum testosterone levels, and the cutoff value for total testosterone levels in LOH ranged from 230–320 ng/dL [20]. LOH guidelines in Japan recommend cutoff values of 250 ng/dL for total testosterone and 7.5 pg/mL for free testosterone as the diagnostic criteria. However, diagnosis of LOH requires comprehensive judgment which includes consideration of clinical symptoms as well as measured values of total testosterone and free testosterone.
TRT has high therapeutic potential. Testosterone replacement increases muscle mass and improves lean body mass and bone density in response to age-related weakness. Testosterone prevents sarcopenia and contributes to muscle maintenance in aging [21]. The effect of TRT among diabetic LOH patients included improved glycemic control and reductions in total blood cholesterol levels and triglycerides [22]. Erectile dysfunction (ED) is a sexual dysfunction disorder resulting from physical pathology, stress response, and partner interactions. In terms of physical pathology, sexual symptoms such as ED, low libido, and reduced nocturnal erectile phenomena have been shown to have a close inverse relationship with testosterone levels [23]. A meta-analysis of the effects of TRT on sexual function suggests improvement of ED, libido, and QOL [24].
In Japan, the most common method of TRT is intramuscular administration, although OTC ointment formulations are also available. Overseas, administration routes include oral and transmucosal (transnasal) as well as intramuscular and transdermal [25].
Drugs which can be used in Japan include the following:
① testosterone enanthate: intramuscular administration of 125–250 mg every 2–4 weeks
② human chorionic gonadotropin: As this drug is utilized when the patient wishes to preserve spermatogenic function and father a child, it falls under the broad definition of testosterone replacement therapy and plays a supplementary role in TRT. Although human chorionic gonadotropin is covered by health insurance for treatment of pituitary hypogonadism, coverage does not extend to male hypogonadism; therefore, use of human chorionic gonadotropin to treat male hypogonadism is at the patient’s own expense. Treatment includes intramuscular administration of 3,000–5,000 units 2–3 times weekly, or once every 1–2 weeks [26].
③ testosterone cream: Note that this is a transdermal supplementary testosterone ointment formulation which is not covered by health insurance in Japan. About 3 mg of testosterone should be applied to the scrotum as well as the skin of the submandibular and abdominal areas once or twice per day. While blood testosterone fluctuates relatively less than with testosterone enanthate, skin irritation may occur [27].
Side effects of TRT include polycythemia, cardiovascular disease, sleep apnea, oily skin, acne, breast pain, liver damage, and infertility. Among these, polycythemia is a comparatively common adverse event [28]. Meta-analysis has found no significant difference in the association of (the presence/absence of) TRT and cardiovascular disease [29]. However, TRT should be carefully considered in patients with cardiac disease as an increased risk of CVEs (cardiovascular events) was noted within the first year of treatment (1.79-fold), particularly among patients over age 65 (2.9-fold).
In terms of TRT-induced polycythemia, higher Hb and Hct levels were observed in healthy subjects who had received increased doses of TRT, with the increase being more pronounced in the elderly than in more youthful subjects [28]. Hb should be monitored regularly during follow-up, particularly during the initial stage, and dose reduction or suspension should be considered when polycythemia become a concern. Gonadotropin suppression via extracorporeal administration of testosterone ultimately suppresses spermatogenesis, leading to spermatogenesis dysfunction. The sperm concentration of 1,045 healthy subjects was examined following a 30-month treatment with testosterone. Azoospermia or oligospermia was observed in 95.2% of the subjects, with sperm concentration recovering an average of 196 days following cessation of testosterone administration [30]. Careful thought should be given in cases in which the subject expresses the wish to father a child as TRT can lead to spermatogenesis dysfunction.
A relatively large number of studies have been conducted to examine whether TRT increases the risk of prostate cancer among patients with LOH. A meta-analysis negated any increased risk of developing prostate cancer from TRT [31]. TRT for LOH normally includes routine blood tests, treatment evaluation, polycythemia and cardiovascular disease risk management, and PSA level follow-up.
ED is defined as the persistent or recurrent inability to obtain or maintain an erection sufficient for satisfactory sexual activity. It is a sexual dysfunction resulting from a physical pathology, stress response, or mutual relationship between partners, and its causes are generally categorized as organic, psychogenic, or mixed. The phenomenon of erection is a coordinated movement of the nervous and vascular systems, and nitric oxide (NO) is important as its transmitter. NO exists in nerve endings throughout the penis and in the vascular endothelium and corpus cavernosum endothelium; impaired NO secretion from these sources hinders the onset and maintenance of erection [32]. From the viewpoint of physical pathology, ED is associated with lifestyle-related diseases such as diabetes, hypertension, and dyslipidemia [33]. Lifestyle factors including aging, obesity, insufficient exercise and smoking, along with low testosterone, are well correlated with metabolic syndrome and cardiovascular disease, impacting patient morbidity. ED is an early symptom of disease causing vascular endothelial damage, and a predicting factor of LOH [34]. TRT is expected to improve ED in cases of hypogonadism and diminished libido. Although there is no consensus on the relationship between androgens and libido, low testosterone is a known risk factor for ED. Oral medications for erectile dysfunction are the preferred choice, but in cases of inadequate response to PDE5 inhibitors, concomitant use with TRT may also be considered [35].
Depression includes the more prevalent and severe major depressive disorder and the less prevalent but more chronic dysthymia. No relationship is reported between testosterone levels and depression in middle-aged and older men, and major studies have negated the possibility that low total testosterone levels increase the risk of developing depression within 1–4 years [36, 37]. However, it is widely assumed that testosterone is decreased in dysthymia [38]. The frequency of LOH syndrome may be increased in dysthymia in middle-aged and older men. A large meta-analysis and systematic review of the effects of testosterone administration in middle-aged and older men with depression was reported in 2018 [39]. A random-effects meta-analysis of 27 randomized controlled trials (RCT) involving 1,890 subjects showed effectiveness (quantitative difference in depression score improvement) in 27 randomized controlled trials (studies evaluating changes in depression before and after testosterone administration, not confined to depressed patients) as well as efficacy (quantitative difference in patient number with depression score improvement of 50% or more) in 7 RCTs. Moreover, while an analysis of factors associated with the degree of effectiveness showed no relationship with the presence/absence of testosterone decline, age (40–59, 60–79, 80 and older), HIV status, severity, treatment duration, or method of administration, a relationship was noted with testosterone dosage (of at least 500 mg/week).
Obesity and metabolic syndrome have been shown to be associated with low testosterone with a bidirectional correlation. In other words, low testosterone causes obesity, and obesity causes low testosterone.
Lipoprotein lipase (LPL), which is found on the surface of adipocytes, degrades triglycerides in the blood and causes them to accumulate in adipocytes, but as testosterone suppresses LPL in adipocytes, adipocyte hypertrophy results when testosterone is low [40]. As testosterone increases the number of β-receptors in adipocytes, inhibiting adipocyte differentiation at the stem cell level and inducing myocyte differentiation, low testosterone results in an increase in adipose tissue [41]. An increase in visceral fat has also been observed in androgen receptor knockout mouse [42].
About 98% of total testosterone is bound to SHBG and albumin, but SHBG, which is synthesized in the liver, has been shown to decrease blood concentration in obesity, diabetes, and metabolic syndrome, and total testosterone is prone to be relatively lower than free testosterone in these conditions [43]. Many suppressions of the hypothalamic-pituitary-testicular system associated with obesity and peripheral pathologies are viewed as reversible, and weight loss is reported to result in improvement. In fact, a 10% weight loss through diet and exercise therapy significantly increased total testosterone levels in the blood [44].
Low testosterone levels are associated with diabetes in men [45]. A lateral study reported that a decrease in blood testosterone levels was an independent factor associated with insulin resistance [46]. In addition, a consistent relationship between a decreased level of SHBG, specific polymorphisms in the SHBG gene and risk of diabetes was reported [47]. Meanwhile, a decrease in blood testosterone level appeared to elevate the risk of metabolic syndrome [48].
TRT is also expected to be effective in metabolic syndrome. TRT efficacy on BMI, waist circumference, lipid metabolism, blood pressure, fasting glucose, insulin resistance, arteriosclerosis, fatty liver, and bone remodeling have been widely reported. Long-term TRT completely prevents prediabetes progression to type 2 diabetes in men with hypogonadism and improves glycemia [49, 50].
As a mechanism, in addition to its direct effect on adipose tissue, TRT also prevents the loss of muscle mass associated with diet therapy and is involved in increasing physical activity due to its positive psychological effects [51].
Although male osteoporosis is often secondary to pre-existing conditions, hypogonadism is one of the key risk factors for secondary osteoporosis, and fractures due to osteoporosis in older men result in higher morbidity and mortality rates than in women [52]. Finkelstein et al. reported that blood testosterone levels less than 200 ng/dL resulted in significantly reduced bone density [53]. Meanwhile, numerous studies on the role of sex hormones on male bone have reported that lower testosterone levels in blood are associated with lower bone density [54]. Bone mass begins a gradual decline in men after age 50, with significant bone loss occurring from around age 70 [55], and TRT efficacy is expected to be higher in men with extremely low baseline blood testosterone levels [56]. Although it has been suggested that TRT may increase bone density, it is not presently indicated as a treatment for osteoporosis. During a short time period, moderate physical activity can elevate testosterone levels in blood while increasing muscle and bone strength, and can aid in preventing falls in older patients [57].
Prostate cancer cells proliferate in an androgen-dependent manner, primarily in older men with low testosterone. Some reports examining the association between blood serum testosterone levels and prostate cancer onset have found no correlation for either testosterone or free testosterone, while others have noted such a correlation. Conversely, low blood serum testosterone levels have been suggested to be involved in prostate cancer stage, the rate of positive margins following radical prostatectomy, and high Gleason score and life expectancy [58]. Our study analyzed data from 235 patients who underwent prostate biopsy and found that blood serum testosterone levels were significantly lower in high-grade prostate cancers with a Gleason score of 7 or greater compared to prostate cancers with a Gleason score under 7 [59].
In a long-term study of 1,365 patients treated with TRT for LOH, only 14 developed prostate cancer. TRT was administered for a median of 6.3 years, a comparatively long duration. Twelve patients had a Gleason score less than four and cT1C, while only two had high-risk but curable prostate cancer [60]. A report of 999 LOH syndrome patients divided into a control group (249 patients) and a TRT group (750 patients) found no difference in prostate cancer incidence [61]. A case-control study by Loeb et al. reported no association between TRT and prostate cancer onset [62]. A retrospective inception study using Veterans Health Administration (VHA) data on 147,593 subjects found no difference in the risk of developing prostate cancer between TRT and non-replacement groups [63]. Even without TRT, prostate cancer is detected upon re-biopsy in approximately 26% of patients with high-grade PIN. Rohden et al. administered TRT for 1 year to 50 patients with benign prostatic hyperplasia (BPH) and 20 patients with high-grade PIN. No significant PSA increase was observed in either group and prostate cancer was detected in only one patient in the high-grade PIN group [64]. Furthermore, a study in which TRT was administered to patients with LOH symptoms during treatment-free observation for prostate cancer reported neither progression of localized prostate cancer nor appearance of metastases [65].
Maintenance of testicular function leads to testosterone maintenance, which aids in the prevention of testosterone-related diseases such as ED and metabolic syndrome. Lifestyle improvements in diet and exercise which prevent or slow age-related testosterone decline may extend healthy life expectancy. Moreover, TRT is expected to have anti-aging effects preventing frailty and improving QOL in older individuals. From the perspective of disease prevention and anti-aging, further functional analysis of testosterone and clinical research development are desirable.
The author has provided disclosure statements on all relationships that he has and that might be perceived to be a potential source of conflict of interest.
