Mobility and Biomechanical Functions in the Aging Male: Testosterone and the Locomotive Syndrome

Abstract

In the current aging society, the occurrence of the locomotive syndrome, a condition in which the locomotive organs are impaired, is increasing. The locomotive system includes support (bones), mobility and impact absorption (joints and intervertebral disks), drive and control (muscles, nerves), and network (blood vessels). The impairment of any of those systems can lead to a major decrease in quality of life. In recent years, several studies on methods to improve and prevent conditions impairing the locomotive syndrome have been conducted. Almost in parallel with the structure supporting mobility and body functions, testosterone levels decrease with age. Testosterone is a hormone-regulating several pathways affecting each aspect of the locomotive syndrome. Testosterone is regulated by the pituitary gland triggering several processes in the body through genomic and non-genomic pathways, affecting muscles, bones, nerves, joints, intervertebral discs, and blood vessels. The purpose of this review is to investigate the role of testosterone in each of the systems involved in the locomotive syndrome.

Keywords:

• Hypogonadism
• aging
• mobility
• sarcopenia
• osteoporosis
• arthritis

Introduction

Due to progress in medical field, the average expectance of life has improved considerably over the last several decades. However, the locomotive functions of the body do often not keep up with that longevity, leading to several impairments in mobility in the elderly. Even though the aging body is relatively healthy, the bones, joints, intervertebral disks, muscles, and nerves regress which cause difficulties in movement, leading to an impaired quality of life. In 2007, the Japanese Orthopaedic Association proposed the name “Locomotive Syndrome” as an inclusive term to describe this condition [1]. This syndrome can ultimately lead to increased morbidity and mortality in the elderly. Indeed, hip fracture due weakened bones or severe sarcopenia can lead to an increased risk in this population becoming bedridden, and the diseases associated with such a state.

For women, osteoporosis occurs in the postmenopausal state or with aging in males. Additionally, secondary osteoporosis is associated with by several endocrine disorders (Hypogonadism, pituitary disorders, diabetes mellitus, thyrotoxicosis, and pregnancy-associated osteoporosis), autoimmune and chronic diseases (Rheumatic disorders, chronic renal disease, chronic pulmonary disease, gastrointestinal diseases, transplantation, granulomatous diseases, and systemic mastocytosis), bone and malignant diseases (Multiple myeloma, lymphomas and leukemias, metastatic bone disease, anemia, and Gaucher’s disease), and smoking and excessive alcohol intake [2]. Currently, several methods of treatment including anti-resorptive treatments (Oestrogen, selective estrogen-receptor modulators, calcitonin, bisphosphonates, and RANKL antibody) and anabolic treatments (Parathyroid hormone or parathyroid hormone-related peptide analogus) [3].

Joint diseases include inflammation of a joint (Arthitis), inflammation of a fluid-filled sac cushioning the joint (Bursitis), and injuries that dislocate the ends of the bones (Dislocations). Joint inflammation is caused by chemicals from the body entering the blood or tissues, increasing the blood flow and causing fluid leaks resulting in swelling, ultimately affecting the nerves and cause pain. Drug therapies for joint pain include Tylenol (acetaminophen), non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, anti-anxiety drugs, antidepressants, and strong pain killers.

Connecting vertebral bodies in the spine, the intervertebral discs regulate load transfers and movements [4]. Degeneration of these discs progresses with aging through a shift in the cellular microenvironment, often leading to lower back pain [4]. Treatments of this condition are often limited to physiotherapy and anti-inflammatory medications [4].

Skeletal muscle is essential for daily activities and movements. However, muscle mass decreases with aging, a phenomenon called sarcopenia [5]. Causes of sarcopenia might be a cascade of steps like (1) decrease of physical activity, (2) impaired protein metabolism, (3) decreases in anabolic hormones (Growth hormone, testosterone, (4) impaired neuromuscular function, (5) altered gene expression, and (6) apoptosis [6]. Treatments for sarcopenia include drug-based pharmaceutical treatments (testosterone, growth hormone, dehydroepiandrosterone, estrogen, ghrelin, vitamin D, angiotensin converting enzyme inhibitor, and eicosapentaenoic acid) and non-drug based treatments (resistance training, protein and amino acid supplementation, and abstinence from smoking) [7].

Decreased lean body mass and increased adipose tissue lead to the metabolic syndrome (MetS) that is associated with higher prevalence of cardiovascular risks. Low testosterone levels have been demonstrated to be associated with MetS diagnosis in non-diabetic men older than 40 y [8]. MetS has been observed in many patients with erectile dysfunction, suggesting an aggravating effect of MetS in combination with hypogonadism on male sexual functions [9]. Furthermore, high prevalence of low testosterone levels has been observed in obese men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia [10], emphasizing the negative relationship between adipose tissue and testosterone levels.

As we can see from the above, several medications are independently used to treat each disease of the locomotive syndrome. On the other hand, it has been recently shown that testosterone administration improves bone mineral density in hypogonadal men with osteoporosis or osteopenia [11]; mitigate joint pain [12,13] enhances chondrogenesis in intervertebral discs [14] and reverses sarcopenia in the elderly [15]. Testosterone replacement therapy has also been shown to positively affect the cardiovascular system in hypogonadal men [16]. Indeed, testosterone improves glucose uptake and metabolism, and therefore, contributes to the prevention of diabetes which is correlated with cardiovascular diseases [16]. For example, a recent study showed that 24 w of testosterone replacement therapy improve insulin-signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) expression in adipose tissue [17]. Anti-inflammatory properties of testosterone have been widely studied in recent years. Pro-inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-α, are major causes of the onset of conditions related to the locomo syndrome (osteoporosis and arthritis) [18]. Testosterone has been shown to be negatively associated with pro-inflammatory markers [19–21]. It has been proposed that testosterone reduces the enzyme phospholipase D activity [22] and therefore, inhibits inflammation. Indeed, a recent study showed that 24 w of testosterone replacements therapy decrease C-reactive protein, IL-β, and TNFα [17]. These results suggest that healthy testosterone levels are important to prevent an increase in pro-inflammatory cytokines and the following diseases.

A recent study investigating testosterone levels, comorbidities, and aging males’ symptoms (AMS) found several correlations among testosterone levels, psychiatric disorders, dyslipidemia, and diabetes mellitus [23], showing again the multiple repercussions of testosterone levels. Another recent study showed that age, AMS score, International Prostate Symptom Score (IPSS), and highly sensitive C-reactive protein (hs-CRP) levels are significantly correlated with the Sexual Health Inventory for Men (SHIM), being an independent factor affecting cardiovascular risk [24]. Low testosterone has also been associated with higher prevalence of depression [25], emphasizing neural effects of testosterone.

The aim of this manuscript is to review the possible application of testosterone replacement therapy as a holistic treatment for several symptoms of the locomotive syndrome.

Aging and decline in testosterone

For males, the decline in testosterone caused by ageing is known as andropause; that is, a partial androgen deficiency of the aging male, and therefore a late-onset hypogonadism (LOH) [26]. Hypogonadism can be divided into primary hypogonadism due to testicular failure and secondary hypogonadism caused by impaired hypothalamic-pituitary-gonadal axis (HPGA). One study showed that 9% of hypogonadal men had primary, 50% had secondary, and 41% had compensated hypogonadism (normal testosterone levels with higher levels of luteinizing hormone (LH) [27].

Aging and primary hypogonadism

In response to pituitary-secreted LH stimulation, testosterone is synthesized by Leydig cells within the testes. In the Leydig cells, LH binds to its receptors the steroid activating receptor is synthesized and cholesterol is carried across the mitochondrial membrane leading to conversion of cholesterol to pregnenolone [28] which travels from the mitochondria to the smooth endoplasmic reticulum where testosterone is synthesized [26]. However, the response of Leydig cells to LH decreases with age [29]. Furthermore, it has been demonstrated that older males have less Leydig cells in their testes as compared with young males [30].

Aging and secondary hypogonadism

Impairments in gonadotropin-releasing hormones (GnRH) which stimulate LH and follicle stimulating hormone (FSH), may lead to a malfunctioning HPGA. GnRH secretion is pulsatile and is produced in the hypothalamus and has been shown to decrease with aging [31].

Joints and testosterone

Cohort studies showed that individuals with arthritis have lower testosterone levels as compared with healthy individuals [32,33]. Another clinical trial showed that men with rheumatoid arthritis have lower bioavailable testosterone, including many hypogonadal individuals [34]. Testosterone replacement therapy has been shown to have protective effects on the progression of arthritis, probably through improved hypothalamo-pituitary-adrenal (HPA) axis response, especially through decreased pro-opiomelancortin mRNA in the anterior pituitary and plasma corticosterone [35]. In osteoarthritis and rheumatoid arthritis testosterone showed favorable anti-inflammatory properties by decreasing aromatization and increase anti-inflammatory 5α-reduced androgens [36]. Indeed, higher levels of estrogen relative to androgens and aromatase conversion products (estrone) have been observed in patients with rheumatoid arthritis [37]. Estrogens have a complex role in inflammation with both pro- and anti-inflammatory actions [38]. As estrogens can be pro-inflammatory and androgens anti-inflammatory, production of 5α-reduced androgens from testosterone might lead to decreased inflammation [39].

Intervertebral discs and testosterone

Intervertebral discs are major parts of the vertebral column, and the mobility of the spine largely depends on the health of disc tissue. Estrogen with its ability to regenerate bone collagen is important to maintain tissues rich in bone and collagen [40]. Recent research showed that testosterone also enhances chondrogenesis of male human intervertebral disc cells [14]. The expressions of aggrecan, collagen type I and II, increased following treatment with testosterone [14]. However, no beneficial effects were observed in female cells [14]. Besides the addition of an aromatase inhibitor (anastrazole) counteracted the effects of testosterone, suggesting that testosterone enhances chondrogenesis of male intervertebral disc cells in part through conversion to estradiol [14].

Muscle and testosterone

Testosterone, through genomic and non-genomic pathways, increases the number of satellite cells and myonuclei, enhances protein synthesis, decreases protein breakdown, improves nitrogen retention and intracellular calcium, and increases the number of red blood cells leading to increased oxygen delivery to the muscles [41], leading to improved muscle mass and quality. Low testosterone levels lead to sarcopenia through increases in oxidative stress, activation of c-Jun NH₂-terminal kinase, and cyclin-dependent kinase inhibitor p21; however, these impairments in muscle mass can be reversed through testosterone supplementation [15]. The role of satellite cells regulated in part by testosterone in muscle repair seems to be very important and might prevent sarcopenia [42]. Indeed, an increase in the number of myonuclei is necessary for muscle repair and or growth; however, the number of myonuclei depends on the number of myogenic precursor cells (satellite cells) located between the basal and plasma membrane of the myofibers [42]. Quiescent satellite cells are activated in response to such exercise and injury but testosterone seems to increase the number of active satellite cells. With increasing age, blood testosterone levels significantly drop and trigger sarcopenia. The loss of muscle mass leads to severe impairments in every day life activities, therefore healthy serum testosterone levels are very important to prevent sarcopenia. Indeed, testosterone replacement therapy is advantageos toward reversing sarcopenia in aging [15].

Erectile dysfunction is related to the aging process and is caused by impaired cavernal smooth muscle cell relaxation, which can worsen if not treated with androgens [43]. The severity of erectile dysfunction seems to be related to mean weight, waist circumference, triglycerides, total cholesterol, HbA1c, fasting glucose, and Aging Males Symptoms (AMS) score [44]. However, testosterone replacement therapy combined with phosphodiesterase-5 inhibitors has shown to improve this condition [45].

Nerves and testosterone

Neuroprotective properties of testosterone have been widely recognized, especially protecting against neurodegenerative disorders such as Alzheimer’s disease, mild cognitive impairment, or depression [46]. Testosterone is also believed to have neurotrophic effects such as neuronal differentiation and enhanced neurite outgrowth following stimulation of androgen pathways in cultured neural cells [47,48]. Protective functions of testosterone have not only been observed in the brain but also in motor neurons. Motor neurons diseases lead to weak skeletal muscles. Motor neurons have been shown to contain androgen receptors, which regulate genomic effects of testosterone [49,50], suggesting a strong influence of testosterone on motor skills. Indeed, a recent study demonstrated that androgen-treated cells grow larger cell bodies and wider neurotic processes. Furthermore, androgen enhance the survival of androgen receptor expressing cells but not control cells, suggesting a trophic role of androgens on motor neurons through androgen receptors [51].

Testosterone and blood vessels

High cholesterol is associated with impairments of the blood vessels. High levels of low density lipoprotein (LDL) can cause a buildup of plaque in the arteries which can lead to narrowing of the vessels and ultimately trigger coronary artery disease. However, high density (HDL) lipoprotein cleans the arteries from LDL and sends it back to the liver. HDL also helps to decrease inflammation and protect the heart. Long-term testosterone replacement treatment results in increased HDL and decreased LDL in hypogonadal men [52], suggesting protective effects of testosterone on arteries.

Natural ways to keep healthy testosterone levels

Each impairment of these building blocks of the locomotive system can be treated separately. However, testosterone replacement therapy might possibly be a holistic treatment for all the symptoms of the locomotive syndrome. Most certainly pharmaceutical means of elevating testosterone in men exist. But, such approaches can have drawbacks and barriers to success. Testosterone can, however, be manipulated in non-pharmaceutical, nature ways too. Specifically, testosterone can be increased through nutrition [53], sleep [54], and resistance training [55].

Dietary high-fat consumption can lead to obesity, which is associated with decreased testosterone levels. One theory proposes that with increasing adipose tissue mass, the expression of aromatase increases, leading to higher conversion rates of testosterone to estradiol, stimulating a negative feedback to the pituitary gonadotropin secretion, and resulting in impaired testosterone levels [56]. A recent study showed that high fat diet causes low testosterone levels through suppression of the testicular leptin and JAK-STAT pathway [57]. Besides, obesity can cause pathological damage of the Leydig cells, oxidative stress in testis tissue, and high leptin levels, ultimately causing secondary hypogonadism [58]. It has been recently suggested that increased inflammation through the interleukin-1-receptor pathway triggers obesity-related hypogonadism [59]. Furthermore, some aspects of testosterone production are regulated by insulin and the development of insulin resistance due to obesity disruption that regulatory loop [60].

Sleep duration is positively correlated to testosterone levels up to ∼9.9 h, after which it decreases [61]. Sleep quality can be improved in individuals with low testosterone, but androgen replacement, but large doses of exogenous testosterone can cause impairments in sleep quality [62].

Resistance training is widely recognized as a very effective tool for increasing muscle mass and strength, those benefits may partly be due to the rise in testosterone they induce even though a direct relationship between resistance training-induced acute raises in testosterone and muscle hypertrophy is still under debate [41]. Nevertheless, some studies observed significant raises in testosterone levels after resistance training [63], and even significant correlations with basal testosterone levels and muscle cross-sectional area after 21 w of resistance training [64]. Interestingly, moderate intensity aerobic has been shown to increase testosterone marginally [65], but large volumes of aerobic (i.e. endurance) training are also associated with suppressed testosterone in men [66].

Put together, the management of risk factors and health can prevent decreases of testosterone [67]. It seems that lifestyle adaptations regarding inclusion of resistance training exercise, nutrition, and sleep can increase muscle mass and testosterone leading to possible preventive and, mitigation of the effects of the locomotive syndrome.

Testosterone replacement therapy as preventive treatment for the locomotive syndrome?

Testosterone levels decrease with aging, leading to several complications including muscle dystrophy, arthritis, osteoporosis, impairment of the spine mobility, diabetes, and cardiovascular diseases. By keeping a healthy testosterone level in elderly, many of these complications might be avoided. Individuals suffering from symptoms above might benefit in consulting a physician and get their testosterone levels checked. Healthy males produce between 2.1 and 11.0 mg of T per day [68]. Testosterone replacement therapy often recommends a weekly administration of 75–100 mg of T or 150–200 mg every 2 w [69] to maintain testosterone levels within a healthy range (400–700 ng/dL) [70]. Testosterone replacement therapy can, therefore, be a powerful treatment to prevent diseases associated with the locomotive syndrome if natural ways to maintain healthy testosterone levels do not function anymore. Indeed, the 2015 European Association of Urology guidelines and several studies suggest that after lifestyle improvements, testosterone replacement therapy may provide several benefits to hypogonadal men including sustained weight loss [71] enhanced body composition, decreased BMI, enhanced sexual function [72] glycemic control, and lipid profile [73] improved. A recent cohort study including more than 800 patients showed that testosterone replacement therapy is safe and well-tolerated in hypogonadic males [74]. However, to avoid relapse, lifelong testosterone therapy might be necessary [73,75]. Several methods of application such as injection, gels, or creams have been proven to be safe and even improve cardiovascular risk factors [76]. Even though numerous methods of treatment are readily available nowadays, a large population of the untreated or not diagnosed men who could benefit from testosterone replacement therapy exists [77].

Conclusion

The progress of modern medicine has led to a major extension in life expectation. However, the quality of life in the elderly largely depends on the extent of their mobility and the ability to live without external help. However, even though organs are healthy, the supporting structure composed of bones, muscles, nerves, joints, intervertebral disks, and blood vessels tend to weaken with increasing age. If one of the structures above does not function properly, the locomotive abilities can be severely impaired, resulting in an increase of morbidity and mortality in the aging population. Despite the existence of pharmaceutical medications for each of those conditions, they often do not cure the disease but only temporarily treat it. On the other hand, testosterone declines with age leading to the downregulation of pathways involved in many aspects of the locomotive syndrome. Therefore, testosterone replacement therapy might be a holistic treatment for each of the mentioned locomotive symptoms.

Declaration of interest statement

The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Figure 1. Relationship between the locomotive syndrome and hypogonadism. GnRH: Gonadotropin-releasing hormone, LH: Luteinizing hormone, FSH: Follicle stimulating hormone.