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GENEMEDICS NUTRITION

Testosterone

Testosterone is a steroid hormone from the androgen group and is present in both men and women as well as in other vertebrates. Testosterone is responsible for physical changes in men during the puberty period such as deepening of the voice, growth of the penis, testes, muscles, facial, pubic and body hair, getting taller and functions to make sperm to be able to have children. [1] In addition, testosterone plays a great role in fat distribution, red blood cell production and maintaining bone density. [2] In women, testosterone is present in smaller amounts. It functions to maintain sex drive, keep bones healthy, manage pain levels and preserve cognitive health. [3]Also, it gives women a sense of motivation, assertiveness and a feeling of well-being.

The brain and pituitary gland (small gland at the base of the brain) control testosterone production by the testes. [4] From there, it moves through the blood to do its work. In women, testosterone is produced in various locations. One quarter of testosterone is produced in the ovaries, a quarter is produced in the adrenal glands, and one half is produced in the peripheral tissues from the various precursors in the ovaries and adrenal glands. [5]

Overall Health Benefits of Testosterone

  • Treats Mood Disorders and Depression [289-303]
  • Fights Type 2 Diabetes [304-316]
  • Prevents Cognitive Decline [317-341]
  • Prevents Osteoporosis and Decreased Bone Density [342-374]
  • Treats Catabolic Wasting [375-396]
  • Improves Symptoms of HIV/AIDS [397-403]
  • Treats Erectile Dysfunction and Low Libido [404-447]
  • Improves Symptoms of Metabolic Syndrome [448-465]
  • Lowers Risk for Heart Diseases [466-480]
  • Normalizes Blood Pressure [481-494]
  • Improves Abnormal Lipid Profiles (Dyslipidemia) [495-503]
  • Treats Rheumatoid Arthritis [504-528]
  • Improves Sleep Quality [529-535]
  • Promotes Fat Loss [536-556]
  • Reduces Wrinkles and Signs of Skin Aging [557-561]
  • Fights Hair Loss [562-566]
  • Improves Quality of Life [567-574]

Testosterone in Men

The levels of testosterone change from hour to hour and vary from person to person. They tend to be highest in the morning (that’s why early morning erections are common) and lowest at night. In general, the normal testosterone levels in males ranges from 270 to 1070 ng/dL. [6] From the age of 30 onwards, total testosterone levels in men decrease by 1% per year. [7]

Testosterone in Women

The production rate of testosterone in normal female is 0.2 to 0.3 mg/day. [8] Normal blood testosterone levels in females can range from 30 to 95 nanograms per deciliter (ng/dL). [9] The testosterone level in women is highest around age 20 and slowly declines until it is half as high in their 40s. [10] For those who had their ovaries removed, testosterone production significantly drops by half, sometimes resulting in less than the normal blood testosterone levels.  

Testosterone Replacement Therapy

Millions of American men use testosterone prescriptions to restore normal levels of the manly hormone and for them to feel more alert, young, energetic, sexually functional, mentally sharp, and to feel good about themselves. An overwhelming body of clinical research has shown that testosterone replacement therapy helps treat signs and symptoms of testosterone deficiency or medically known as hypogonadism. Depending on the nature and severity of testosterone deficiency, doctors may prescribe testosterone in the form of injections, pellets, tablets, patches, or gels.

Andropause

Testosterone levels generally peak during the adolescent period and early adulthood. As men age and when they reach andropause or sometimes called male menopause (usually between the ages of 40 and 80 above), they can experience a number of symptoms related to natural decline in testosterone levels. [11]

One of the most common symptoms is a decrease in sexual function. They experience reduced sex drive, fewer erections, hot flashes and infertility. Other physical changes related to low testosterone levels include increased body fat, decreased muscle mass and body hair, fragile bones, swelling or tenderness in the breast tissue, increased fatigue and has an effect on cholesterol metabolism. [12]

Despite the fact that low testosterone can cause decreased energy levels, it can also cause insomnia and changes in sleep patterns. Affected individuals can also experience emotional changes such as feelings of sadness or depression, low self-esteem and motivation, lack of concentration or focus, and an overall decrease in sense of well-being. While each of these symptoms is related to low testosterone level, they may also be related to other medical conditions such as thyroid problems, autoimmune disorders, side effects of medications and mental problems.

Insufficiency

Hypogonadism or testosterone deficiency is a condition in which the body does not produce sufficient levels of testosterone as a result of an underlying medical condition or other causes. It is likely that testosterone deficiency is underdiagnosed and is often mistaken for other medical conditions due to the fact that its signs and symptoms resemble other diseases, especially psychiatric disorders.

Testosterone deficiency is classified according to the location of its cause: [13]

  • Primary: This type of testosterone deficiency is also known as primary testicular failure. The causes of the deficiency originate from a testicular problem.
  • Secondary: In this type of testosterone deficiency, the testicles are normal but its functions are altered due to a problem with the pituitary gland or hypothalamus (brain region that regulates temperature).

Hypogonadism may be present at birth (congenital) or may develop later in life (acquired). Congenital causes of hypogonadism include the following:

  • Klinefelter’s Syndrome: This condition results from a congenital abnormality of the sex chromosomes, X and Y. Normally, a male only has one X and one Y chromosome. [14] In this condition, two or more X chromosomes are present in addition to one Y chromosome. This causes the testicles to develop abnormally, which in turn affects the production of testosterone.
  • Undescended testicles (Cryptorchidism): Normally, the testicles move down the scrotum after birth. [15] Sometimes, one or both of the testicles may not descend and remain inside the abdomen. If not corrected in early childhood, it may affect the function of the testicles and reduce the rate at which testosterone is produced.
  • Kallmann syndrome: This condition is referred to as an abnormal development of the hypothalamus. [16] This abnormality can also affect the ability to smell (anosmia) and can lead to red-green color blindness.
  • Hemochromatosis: This condition occurs when there is too much iron in the blood. [17] As a result, the testicles or pituitary gland malfunctions, affecting the production of testosterone.

Acquired causes of testosterone deficiency include the following:

  • Injury or trauma to the testicles:This can impair blood flow going to the testicles and affect the production of testosterone.
  • Cancer treatment: Chemotherapy or radiation therapy can interfere with the production of sperm and testosterone. [18] Although the effects are temporary, there is still a chance that permanent infertility may occur.
  • Pituitary disorders: Any abnormality in the pituitary gland such as tumors can hinder the release of hormones from the pituitary gland to the testicles, thus affecting the production of testosterone.
  • Inflammatory disease: Tuberculosis, sarcoidosis and histiocytosis can affect the hypothalamus and pituitary gland, which in turn impair the production of testosterone. [19]
  • Autoimmune disorders: HIV/AIDS (Acquired immunodeficiency syndrome) can impair testosterone production by affecting the hypothalamus, the pituitary gland and the testes. [20]
  • Medications: Long-term use of medications for high cholesterol such as statins can lower testosterone levels as a side effect. [21]
  • Stress: Chronic stress raises the levels of the stress hormone called cortisol in response to the situation. This in turn suppresses the central hormone pathways which includes testosterone. [22]

Testosterone Replacement Therapy in Men

Most healthcare providers worldwide prescribe testosterone replacement therapy (TRT) as a therapeutic option for men who are suffering from chronic, debilitating symptoms of hypogonadism. An overwhelming body of evidence-based studies supports the following therapeutic benefits of TRT:

  • Improves blood pressure[23-41]
  • Improves blood sugar levels [42-52]
  • Improves bone health [53-83]
  • Improves cholesterol levels [84-96]
  • Improves concentration, memory and thinking skills [97-116]
  • Improves energy levels and mood [117-125]
  • Improves fat loss [126-135]
  • Improves sex drive and performance [136-143]
  • Improves sleep quality [144-150]
  • Increases muscle mass and improves body composition [151-165]
  • Treats inflammatory disorders [166-182]
  • Reduces wrinkles and other signs of skin aging [183-184]
  • Prevents age-related hair loss [185-186]
  • Improves quality of life [187-191]

Testosterone Replacement Therapy in Women

In women, testosterone may have a direct effect on libido and sexual response. Research shows that testosterone replacement therapy for women does impact sex drive and may help reduce symptoms associated with sexual dysfunction in women. [192-193] The prescription of testosterone for women might be appropriate if:

  • You have reduced sexual desire, depression, extreme fatigue, and mood changes after surgically induced menopause (surgical removal of the ovaries), and estrogen hormone therapy does not relieve your symptoms. [194]
  • You are postmenopausal and on estrogen therapy and have a decreased libido with no other identifiable causes. [195]

Aside from improving sex drive, TRT in women has the following proven health benefits:

  • Decreases body fat [196-198]
  • Decreases muscle stiffness and joint pain [199-210]
  • Improves blood sugar levels [211-213]
  • Improves blood pressure [214-230]
  • Improves cholesterol levels [231-237]
  • Improves bone density and strength [238-253]
  • Improves energy levels and mood [254-259]
  • Improves concentration, memory and thinking skills [260-265]
  • Improves muscle tone, strength and endurance [266-272]
  • Improves sleep quality [273-276]
  • Treats inflammatory disorders [277-283]
  • Reduces wrinkles and other signs of skin aging [284-285]
  • Prevents age-related hair loss [286]
  • Improves quality of life [287]

Proven Benefits of Testosterone Therapy for Specific Health Conditions

Increased longevity and population aging will increase one’s risk of developing late onset hypogonadism. It is a common condition, but is often mistaken for other medical condition that’s why it is underdiagnosed and undertreated. The indication of testosterone replacement therapy requires the presence of below the normal testosterone level, and signs and symptoms of hypogonadism. TRT may produce a wide array of benefits for those with testosterone deficiency including improvement in sexual desire and function, muscle mass, bone density, body composition, cognition, mood, erythropoiesis (red blood cell production), heart function and quality of life. [288]

Treats Mood Disorders and Depression

Testosterone can alter a person’s mood if it falls below the normal level. Researchers first noticed the effects of low testosterone in animals. The researchers observed that males with decreased testosterone become much more aggressive and prone to fighting instead of becoming docile and quiet. [289] Since then, they have studied this effect in different kinds of mammals and in humans. Interestingly, growing scientific evidence shows that testosterone replacement therapy does have a positive effect in improving the mood of men and women who are suffering from anxiety, depression, stress, and other mood disorders.

Numerous studies even found that low levels of testosterone are associated with a higher risk of depression in men and women. [290-292] This strongly suggests that testosterone supplementation may significantly boost the overall mood as well as quality of life of people suffering from depressive symptoms. Furthermore, results from these high quality studies clearly indicate that having healthy testosterone levels dramatically lowers one’s risk for mood disorders.

Generally, questionnaires are used to monitor psychological items such as positive mood responses and negative mood responses. [293] Other studies have assessed similar attributes such as being angry, alert, energetic, irritable, tired, sad, nervous, and changes in well-being. [294] Changes in mood parameters such as having low mood are generally experienced by hypogonadal men. In order to correct this, testosterone replacement therapy is usually prescribed because of its antidepressant effect. To prove the therapeutic benefits of testosterone on depression, Zarrouf et al. conducted both a systematic review of literature and a meta-analysis of studies exploring the antidepressant effect of testosterone. [295] The results of the meta-analysis of the data from seven studies showed a significant positive effect of testosterone therapy on Hamilton Rating Scale for Depression (HAM-D) response in depressed patients when compared with placebo.

A related study by Pope et al. also showed improvement in scores on the Hamilton Depression Rating Scale in men who had refractory depression and low or borderline testosterone levels who received transdermal testosterone gel supplementation for 8 weeks than subjects receiving placebo. [296]

Testosterone can even surpass the effects of anti-depressants such as Selective serotonin reuptake inhibitor (SSRI) in minimizing the symptoms of depression. In one study, Seidman et al. reported that 400 mg of testosterone replacement biweekly for 8 weeks in five depressed men who had low testosterone levels and had not responded to SSRI, showed improvements in depressive symptoms. [297]

Studies also show that testosterone does have beneficial effects on mood disorders such as bipolar disorder, a mental disorder marked by alternating periods of elation and depression. A study by Wooderson et al. found that men with bipolar disorder had significantly lower testosterone levels, suggesting that healthy testosterone levels may prevent this mood disorder. [298]

Another study conducted by Kawahara et al. also found that testosterone therapy is beneficial in alleviating psychiatric symptoms in patients who are unresponsive to mood stabilizers and second-generation antipsychotics. [299]

Low testosterone levels have also been associated with anxiety and poorer sense of psychological well-being, which ultimately leads to impaired quality of life. Interestingly, numerous high quality studies show that testosterone does have anti-anxiety effects, and that testosterone supplementation is beneficial in alleviating symptoms of anxiety and improving quality of life of older men and women. [301-303]

Fights Type 2 Diabetes

Over the years, researchers found out that there is a significant connection between low testosterone and diabetes. In fact, men with type 2 diabetes are twice as likely to have low testosterone levels compared to men who don’t have diabetes. [304] Low levels of testosterone in men are associated with insulin resistance or reduced insulin sensitivity. [305] Insulin resistance is a medical condition wherein your body produces insulin but does not use it properly. This in turn lead to accumulation of blood sugar in the bloodstream rather than being absorbed by the cells to be used as a source of energy. Over time, insulin resistance can lead to type 2 diabetes and other health problems.

There is increasing evidence that testosterone can help improve blood sugar levels by correcting insulin resistance. For instance, a study conducted by Kapoor et al. investigated the effect of testosterone treatment on insulin resistance and glycaemic control (blood sugar levels) in 24 hypogonadal men aged 30 and above with type 2 diabetes. [306] The researchers found that testosterone replacement therapy reduced insulin resistance and improved blood sugar levels in all participants.

A similar study involving 48 middle-aged men (24 subjects received testosterone undecanoate for 3 months and 24 did not) with type 2 diabetes and symptoms of testosterone deficiency showed that oral testosterone undecanoate treatment improves blood sugar levels, decreases visceral obesity and improves symptoms of testosterone deficiency including erectile dysfunction. [307] In all of the participants, the benefit of oral testosterone supplementation therapy exceeded the correction of symptoms of testosterone deficiency.

Several interventional trials have also reported that testosterone improves blood sugar levels in people with type 2 diabetes by reducing the levels of various inflammatory markers, improving visceral obesity, and enhancing the body’s response to the effects of insulin. [308-310] Improvements in these parameters can also improve one’s quality of life by lowering one’s risk of diabetes as well as other fatal disorders. In fact, in a study of 581 diabetic males who were followed up for several years, Muraleedharan et al. found that men with low testosterone levels had a high mortality rate of 17.2% as compared with 9% in men with normal testosterone.    [311-315]

Other high quality studies have also shown that testosterone replacement therapy may help improve symptoms of diabetes by stabilizing blood sugar levels and improving the body’s response to the effects of insulin. [316] These beneficial effects ultimately lead to a lower risk of complications from diabetes and improved quality of life.

Prevents Cognitive Decline

As testosterone declines with age, so does cognitive function. Older men and women may experience deterioration in their memory, attention, language and visuospatial ability. The prevalence of cognitive dysfunction in the aging population is high. According to statistics, moderate to severe memory impairment has been estimated to occur in about 13% of adults aged 65 years and above, and in 32% of adults aged 85 years and above. [317]

Researchers have suggested that the age-related declines in cognitive function and testosterone are closely related. [318] Numerous studies suggest that cognitive impairment is a component of late-onset hypogonadism, for which some men may undergo testosterone replacement therapy.   [319-321]Other studies also concluded that low levels of testosterone may be related to reduced cognitive ability, and testosterone replacement therapy may improve some aspects of cognitive ability. [322-327]

Treating older men with testosterone may help improve spatial intelligence (deals with judgment and the ability to visualize) and verbal memory, according to a small study conducted by researchers at the University of Washington in Seattle. [328] The results of this study clearly suggest that restoring testosterone to healthy levels may improve cognition.

In another study, Cherrier et al. investigated the effects of 6-week testosterone supplementation via injection among 19 men aged 63 to 85 years with Alzheimer disease (AD) or mild cognitive impairment (MCI). [329] Improvements in spatial memory, constructional abilities and verbal memory were evident as their levels of testosterone increased by an average of 295%.

In a related study by Ackermann et al., healthy subjects encoded pictures taken from the International Affective Picture System (IAPS) and they underwent a free recall test 10 minutes after memory encoding. [330] The study revealed that higher levels of testosterone were related to increased brain activation and that testosterone has a male-specific role in enhancing memory by increasing the biological salience of incoming information.

Higher testosterone levels also offer great benefits on the brain. One study referenced in the Harvard Men’s Health Watch found that higher levels of testosterone in middle-aged men were associated with preservation of brain tissue in different regions later in life. [331] In this way, brain aging as well as cognitive decline can be slowed.

In a study by Anawalt et al., testosterone was found to activate a network in the brain which helps improve cognition as well as verbal and visual memory. [332] Researchers believe that this mechanism helps boost cognitive health in elder men and women.

Not only does testosterone supplementation helps support cognitive health. A study by Wahjoepramono et al. found that testosterone supplementation can also significantly reduce the risk of dementia, a condition characterized by a decline in memory or other thinking skills. [333] This may be due to the fact that testosterone supplementation in the study participants resulted in improved performance on various measures of cognitive functioning.

In line with the above findings, there is also an overwhelming body of clinical research that supports the safety and efficacy of testosterone replacement therapy in improving various parameters of cognitive health, including memory, attention, language, visuospatial ability, and thinking skills, in patients with testosterone deficiency and age-related decline in cognitive function. [334-341]

Prevents Osteoporosis and Decreased Bone Density

The integrity of the skeletal system is maintained by a complex process known as remodeling. The process of bone remodeling is governed by three major types of bone cells: bone-forming osteoblasts, bone-resorbing osteoclasts, and mediator osteocytes. [342] These bone cells are very sensitive to signaling conveyed through hormones, particularly testosterone. Dysfunction of these cells is the primary cause of dysregulation of the remodeling process, which ultimately lead to bone loss and bone disorders.

As men age, their testosterone concentrations in the blood start to decline, as do their bone densities. Because testosterone plays a crucial role in the signaling of the bone cells, the age-related decline in this hormone may ultimately lead to dysregulation of the bone remodeling process. This in turn causes osteoporosis, a bone disease characterized by weak and fragile bones. Researchers found that there is a high incidence of early bone loss and low bone density (osteopenia) in men with low levels of testosterone which increases their risk of osteoporosis. [343] And the longer the duration of testosterone deficiency, the greater the risk.

Sex steroids in both sexes play a pivotal role in the maintenance of bone quality. Numerous high quality studies even found that low testosterone levels are associated with a higher risk of osteoporosis and other bone disorders. [345-349] It seems reasonable to anticipate that low levels of testosterone in aging men and women would correlate to a loss in bone mineral density (BMD) and an increase in the risk of fractures, and that testosterone replacement therapy may have beneficial effects on bone quality.

Because bone density is also low in hypogonadal men, testosterone replacement therapy would help restore bone density to healthy levels. In one study investigating the effect of testosterone treatment on bone mineral density in men over 65 years of age, Snyder et al. reported that testosterone patch did increase bone mineral density of the lumbar spine as well as blood testosterone concentrations after 36 months of treatment. [350]

In a similar study, Amory et al. investigated the effects of testosterone therapy and finasteride, a 5 alpha-reductase inhibitor (prevents conversion of testosterone), among 70 men aged 65 years and older with low testosterone levels for over 36 months. [351] The study showed that the combination of testosterone therapy and finasteride increased vertebral and hip bone mineral density (BMD), which is indicative of improved bone quality.

Growing evidence also suggest that testosterone replacement can be beneficial in improving bone mineral density and lowering fracture risk in men with osteoporosis and hypogonadism. In fact, the Endocrine Society of North America recommends testosterone replacement therapy in symptomatic hypogonadal males to improve their symptoms and enhance bone mineral density. [352] This recommendation appeared in their clinical guidelines in 2010. Moreover, the 2012 Endocrine Society Osteoporosis in Men guideline also recommends testosterone replacement therapy in men with symptomatic low testosterone who are at high risk of fracture. [353]

There also have been a number of clinical trials assessing the effect in men of testosterone replacement therapy on bone quality and strength, regardless of underlying testosterone levels, which generally resulted in a significant improvement in bone mineral density. In one study, Hoppéa et al. conducted a review of 14 clinical trials assessing the beneficial effects of testosterone replacement therapy in men, all of which looked at bone mineral density at the lumbar spine and femoral head, without fracture risk outcomes. [354] With regards to the bone mineral density of the lumbar spine, 5 out of the 14 clinical trials showed significant increases. Because of these positive results, the authors concluded that there was sufficient evidence to support the benefit of testosterone replacement therapy in lumbar spine bone mineral density.

There also have been additional studies in men that have provided further strong evidence for the therapeutic benefit of testosterone replacement therapy on lumbar spine and femoral bone mineral density. For instance, a study by Permpongkosol et al. evaluated the effects of testosterone treatment in 120 late-onset hypogonadal males (mean age is 65.6 years old). [355] The study participants received intramuscular testosterone injections for 5 to 8 years, the longest study to date. Surprisingly, researchers observed a significant increase in bone mineral density of the lumbar spine and femoral neck after 48 months of treatment.

Other studies have also shown that aside from injections, testosterone treatment may also be effective if taken orally or applied to the skin. In a study by Wang et al., oral low dose testosterone treatment among 186 hypogonadal males aged 60 and above with osteoporosis at baseline, resulted in significant increases in the bone mineral density of the lumbar spine and femoral neck after 6 to 12 months. [356]

A similar study by Bouloux et al. involving 322 hypogonadal males aged 50 and above found that intermediate and high doses of oral testosterone resulted in significant increases in bone mineral density of the lumbar spine, total hip, trochanter (upper part of the thigh bone), and intertrochanteric sites. [357]

Also, a study by Rodriguez-Tolra et al. found that application of topical testosterone gel among 50 hypogonadal males aged 50 and above resulted in significant increases in the bone mineral density of the lumbar spine at both 12 and 24 months, and in the total hip and trochanter at 24 months only. [358]

Numerous clinical trials have also shown that testosterone replacement therapy may significantly increase bone mineral density in different body parts and reduce the risk of fractures as well as other bone disorders. [359-374]

Treats Catabolic Wasting

When a person suffers from loss of muscle and fat tissue due to chronic illness, this condition is called cachexia. [375] The general loss of weight and muscle mass that naturally occurs with advancing age is called sarcopenia. [376] The term “catabolic wasting” encompasses both of these medical conditions.

Testosterone plays a critical role in muscle building and maintaining muscle mass, and many muscle-wasted patients are deficient in testosterone. [377] A study by Hager et al. even reported that testosterone levels were deficient in over 70% of men with cancer cachexia. [378]The researchers observed that total testosterone levels were lower in cancer patients with cachexia compared to cancer patients without cachexia.

Another study by Yuki et al. demonstrated a significant relationship between baseline testosterone and muscle mass changes in Japanese men. [379] Data were collected from community-dwelling 957 adult men who participated in the study from 1997-2010. Interestingly, the researchers concluded that low free testosterone may be a predictor of risk for muscle loss in Japanese men.

Hypogonadism is common in patients undergoing hemodialysis and is associated with higher doses of medications, reduced muscle mass and lower physical activity. In a study conducted by Cobo et al., a strong link between low testosterone levels and physical inactivity was found which is believed to conceivably relate to reduced muscle mass due to inadequate muscle protein synthesis. [380]

Since testosterone is known to boost muscle protein synthesis, muscle mass and strength, several researchers concluded that the decrease in testosterone may ultimately result in loss of muscle mass, especially in the older population where testosterone decline is a normal part of the aging process. With this in mind, several studies have investigated the effect of testosterone replacement therapy in older men with abnormally low testosterone concentrations.

For instance, a study by Tenover et al. found that intramuscular testosterone enanthate injections at a dose of 100 mg weekly for 3 months among healthy men, 57-76 years old, who had low or borderline blood testosterone levels, resulted in an increase in lean body mass. [381] This result suggests that testosterone supplementation may have a beneficial effect on age-related loss of muscle mass.

In another study assessing the effects of testosterone replacement therapy on older hypogonadal men (mean age 76 years), Morley et al. found that subjects who received testosterone enanthate injections at a dose of 200 mg/ml every 2 weeks for 3 months, had a significant increase in testosterone and bioavailable testosterone concentration, as well as right hand muscle strength, suggesting that testosterone treatment doesn’t only improve muscle mass but also muscle strength. [382]

In a similar study by Katznelson et al., testosterone enanthate injections at a dose of 100 mg/week for 18 months among 29 hypogonadal men significantly decreased body fat percentage and increased lean muscle mass without any adverse side effects. [383] These beneficial effects of testosterone provide additional indications for testosterone therapy in hypogonadal men.

Other studies also provide stronger evidence that other route of testosterone administration may also be beneficial in preventing age-related muscle loss. For instance, Ly et al. reported that daily skin application (transdermal) of 70 mg testosterone gel in older men with testosterone deficiency was able to improve lower limb muscle strength without any adverse effects. [384]

In a similar study, Kenny et al. found that transdermal testosterone at a dose of 5 mg/day decreased body fat and increased lean body mass in a group of healthy men over age 65 with low bioavailable testosterone levels. [385]

Not only does testosterone helps treat age-related loss of muscle mass and strength, it can also help build muscle and prevent further muscle loss caused by specific medical conditions. Gullet et al. reported that testosterone replacement therapy has been useful in promoting lean weight gain for patients with HIV/AIDS- or COPD-related cachexia. [386] Because loss of body weight, lean body mass, and fat tissue significantly increases these patients’ risk of dying from complications, testosterone supplementation can therefore prevent this from happening.

Studies even show that the oral testosterone derivative oxandrolone has been used for several years as a therapeutic intervention against unintentional weight loss associated with HIV/AIDS-related muscle wasting. [387] In a double-blind, randomized study, oxandrolone at doses of either 5 mg or 15 mg daily was effective in improving body weight and well-being in 63 HIV-positive men with weight loss of more than 10% of initial body weight. [388]

An overwhelming body of clinical research even found that testosterone may help improve muscle mass, strength and function in older persons with sarcopenia related to various health conditions. [389-394] Specifically, studies show that testosterone supplementation can prevent muscle wasting and improve functional capacity in patients with heart failure as well as testosterone deficiency. [395] In patients with chronic kidney disease, testosterone can also help improve handgrip strength and increase fat-free mass, suggesting that testosterone supplementation has a holistic positive effect on muscle mass, strength and function. [396]

Improves Symptoms of HIV/AIDS

Most HIV-infected men have testosterone deficiency. [397] Treatment of hypogonadal HIV-infected men with testosterone supplementation can lead to increased muscle mass and improvements in depression as well as quality of life. In HIV-infected women, testosterone treatment has shown improvements in weight and social functioning. [398]

In one study involving seventy-four HIV-infected patients who received bi-weekly testosterone injections followed by 12 weeks of open-label maintenance treatment for a period of 6 weeks, the results showed improvement in symptoms of clinical hypogonadism, thus restoring sex drive and energy, alleviating depression, and increasing muscle mass. [399]

In another study, Coodley et al. reported that 200 mg of testosterone cypionate injections every 2 weeks for 3 months in HIV-infected patients did appear to produce an improved overall sense of well-being and muscle strength. [400] Researchers observed that the testosterone treatment did not produce any adverse side effects.

A study by Kong et al. assessed the effects of testosterone therapy on different body parameters of patients with HIV wasting syndrome. [401] After the treatment period, researchers observed that the patients had significant improvements in lean body mass, total body weight, over-all exercise functional capacity, and perceived quality of life without any adverse side effects.

Gains in strength in all exercise categories and greater increase in thigh muscle volume were also observed by Bhasin et al. in HIV-infected men who received testosterone therapy. [402] The average lean body mass increased by 2.3 kg in the testosterone-treated group compared to those who received placebo.

In one large clinical trial, Blick et al. reported that HIV-infected men who received testosterone therapy for 12 months experienced significant elevations in total testosterone and free testosterone levels to within normal ranges. [403] In addition to this, the study participants also had significant improvement in sexual function, depression scores and body composition, and   antidepressant medication use decreased in the testosterone-treated group.

Treats Erectile Dysfunction and Low Libido

Erections are clearly androgen-dependent. Testosterone has always been assumed to play a major role in erectile dysfunction (ED) because of the following reasons:

  • A decline in testosterone levels happens with ageing and a time period when the incidence of ED increases. [404]
  • Castration usually leads to impairment in sexual function. [405]
  • Sexual function returns to normal in castrated men with severe testosterone deficiency who undergo testosterone replacement therapy. [406]

A number of high quality studies clearly support the benefits of testosterone replacement therapy in men with ED. In one study assessing the benefits of testosterone for ED, Kalinchenko et al. reported that combining oral testosterone undecanoate with anti-diabetic drugs in diabetic patients who do not respond to Viagra therapy, has been observed to restore sexual function. [407] This strongly suggests that testosterone is more potent than drugs for ED.

In a double-blind placebo controlled, cross-over study, Schiavi et al. treated healthy men with erectile dysfunction with biweekly injections of 200 mg of testosterone enanthate for over a period of 6 weeks separated by a washout period of 4 weeks. [408] Results suggest that testosterone administration among the subjects was able to increase ejaculatory frequency, reported sexual desire, masturbation, sexual experiences with partner, and sleep erections.

A recently published, multicenter study by Shabsigh et al. evaluated the safety and efficacy of testosterone gel in conjunction with sildenafil, a drug for ED. [409] The study involved hypogonadal men who did not respond to treatment with sildenafil alone for erectile dysfunction. After 12 weeks of testosterone gel therapy, the participants reported improved erectile response to sildenafil, suggesting that testosterone therapy may be considered for the treatment of ED in men with low testosterone levels, who have failed prior treatment with sildenafil alone.

In one meta-analysis covering several studies, Isidori et al. reported that the effect of testosterone replacement therapy in men with ED was directly related to blood levels of testosterone. [410] When compared to placebo, study participants who benefited most from the therapy were those with lower blood levels of testosterone, and those with near the normal testosterone levels had no benefit at all.

Larger meta-analyses of studies assessing the clinical benefits of testosterone concluded that testosterone therapy was able to increase libido in seven of eight studies and improved erections in five of six studies. [411] Interestingly, most of these studies report that testosterone replacement therapy has no adverse side effects.

In a well-designed intervention study, Aversa et al. reported that testosterone does have a specific mechanism of action on the erectile tissues of the penis. [412] The researchers assessed the effects of testosterone administration in 20 patients with ED who failed to respond to treatment with sildenafil. After the study period, treatment with transdermal testosterone raised the blood testosterone levels of the patients and led to an increase of arterial blood flow into the erectile tissues of the penis. This effect led to improvement in the symptoms of ED and enhanced the response to treatment with ED drugs.

In line with the above findings, Foresta et al. have documented that normal blood testosterone level is required for proper erectile function. [413] In severely hypogonadal men, the nocturnal penile tumescence (spontaneous erection of the penis during sleep or when waking up), ultrasound measurement of arterial blood flow within the erectile tissues of the penis, and visually stimulated erection in response to ED drugs were minimal. Surprisingly, the researchers reported that these parameters were normalized after six months of administration of testosterone patches, evidencing the crucial role of normal blood levels of testosterone for proper erectile function.

There are also numerous clinical trials that support the safety and efficacy of testosterone replacement therapy in treating low libido in both men and women. Results from these clinical trials have shown that men and women who received testosterone replacement therapy had better scores in various tests assessing sexual function, had increased sexual desire and improved self-confidence. [414-447]

Taken together, these available data suggest that higher circulating levels of testosterone are essential for normal erection and that testosterone replacement therapy may help improve low libido. Therefore, screening for hypogonadism in men and women with reduced libido and sexual dysfunction is crucial to identify the severity of testosterone deficiency and determine which patients may benefit from testosterone replacement therapy.

Improves Symptoms of Metabolic Syndrome

Metabolic syndrome (MetS) is a cluster of conditions including high blood pressure and blood sugar level, abnormal cholesterol levels, and excess body fat around the waist. This medical condition is one of the main threats for public health in the 21st century. According to the International Diabetes Federation (IDF), 20-25% of the adult population worldwide has MetS. [448] Having MetS increases one’s risk of developing chronic medical conditions such as diabetes and cardiovascular disease.

An overwhelming body of clinical evidence has shown a higher prevalence of MetS in subjects with low testosterone. [449-455] This may be due to the fact that low testosterone also increases one’s risk for high blood pressure, high blood sugar, abnormal cholesterol, and obesity. This constellation of risk factors, constitute MetS.

Restoring low testosterone levels through testosterone replacement therapy may help improve symptoms of MetS. One of the earliest studies reporting the effect of testosterone replacement therapy on risk of factor of Mets was by Rebuffescrive et al. in 1991 where they found that the therapy decreased waist-hip ratio in 9 out of 11 men after 6 weeks. [456] Recently, there have been a number of studies published assessing the therapeutic benefits of testosterone replacement therapy in patients with MetS.

Heufelder et al. investigated the effects of supervised diet and exercise with or without testosterone administration among 32 hypogonadal men for a period of 52 weeks. [457] The study resulted in greater therapeutic improvements of blood sugar levels.

A related study conducted by Jones et al. among 220 hypogonadal men with type 2 diabetes and/or MetS who are on testosterone replacement therapy (TRT) over a 6-month period, has shown beneficial effects on insulin resistance, total and LDL-cholesterol (Low Density Lipoprotein), and sexual health. [458]

A single-blind randomized study of testosterone administration in men with MetS and recent onset of diabetes mellitus also resulted in significant improvements on blood pressure over and above the effects of diet and exercise. [459] The men treated with testosterone also reported increased well-being and energy.

In a study by Saad et al., they found that testosterone administration among elderly men with late-onset hypogonadism had beneficial effect on sexual dysfunction and symptoms of MetS. [460] In addition, they also observed that the higher plasma levels of testosterone generated with long-acting testosterone undecanoate were clearly more effective in achieving therapeutic effect than testosterone gel.

In a large multicenter study undertaken in eight European countries, the TIMES2 (Testosterone replacement In men with Metabolic Syndrome or type 2 diabetes), Jones et al. reported that the treatment improved insulin resistance and cholesterol levels, and reduced body fat percentage after 6 and 12 months of therapy. [461] Researchers concluded that testosterone replacement therapy in men with MetS is superior to placebo treatment and does not have any adverse side effects.

In another study, Francomano et al. treated 20 hypogonadal men with testosterone undecanoate injections every 12 weeks for 60 months. [462] After testosterone treatment, study participants experienced significant reductions in MetS parameters such as waist circumference, body weight and blood sugar level, and improvements in insulin sensitivity, lipid profile, systolic and diastolic blood pressure.

A 5-year study by Yassin et al. involving two hundred sixty-one patients diagnosed with late-onset-hypogonadism and erectile dysfunction, has shown that treatment with injectable testosterone undecanoate significantly decreased weight, waist circumference, blood pressure, HbA1c (a measure of blood sugar level), triglycerides and low density lipoprotein cholesterol (bad cholesterol). [463] In addition to this, there was a significant increase in high-density lipoprotein cholesterol (good cholesterol) observed after the treatment period.

A registry of 255 men, aged between 33 and 69 years with abnormally low blood levels of total testosterone and the MetS assessed the effects of testosterone treatment in these medical conditions. [464] All men were treated with injectable testosterone undecanoate 1000 mg at baseline and 6 weeks and thereafter every 12 weeks for up to 5 years. Interestingly, researchers observed that testosterone therapy restored physiological testosterone levels and resulted in reductions in total cholesterol, low-density lipoprotein cholesterol and triglycerides, and increased high density lipoprotein cholesterol levels. There were also marked reductions in systolic and diastolic blood pressure, as well as blood sugar levels.

Finally, a study by Bhattacharya et al. evaluated the effects of testosterone gel in men with and without the MetS for 1 year. [465] They observed that only patients with the MetS demonstrated decreases in waist circumference, blood sugar levels, and blood pressure. Significant decreases in these parameters were seen in patients in the lowest total testosterone quartile, suggesting that testosterone treatment has beneficial effects in patients suffering from MetS.

Lowers Risk for Heart Diseases

Cardiovascular disease (CVD) is the leading cause of death globally, with an estimated 17.5 million deaths in 2012. [466] CVDs primarily affect the heart tissues and are precipitated by non-modifiable as well as modifiable risk factors. Recently, emerging risk factors such as low testosterone levels have been suggested to contribute to the development of CVD. [467-468] These studies have emphasized that people with lower testosterone levels are at increased risk of developing CVD and dying from this condition.  [469-471]   

For instance, a study by Malkin et al. involving over 900 men found that both total and bioavailable testosterone were significantly lower in men with coronary artery disease compared to those without heart disease. [472] The same study demonstrated a prevalence of low testosterone levels of 24% in men with coronary artery disease.

In the Rotterdam study, Hak et al. evaluated the association between total and bioavailable testosterone and aortic atherosclerosis (narrowing of the heart’s muscular pumping chamber) in 504 non-smoking men aged 55 years and above. [473] Researchers found that men with the highest testosterone levels had a risk reduction of 60–80% of severe aortic atherosclerosis compared to those with lower testosterone levels.

Another prospective study conducted by Muller et al. involving elderly men (mean age 77 years) showed that lower level of free testosterone is related to progression of intima–media thickness of the common carotid artery over 4 years. [474] This means that lower testosterone levels are strongly linked with narrowing of the arterial walls of the heart, which ultimately leads to poor blood circulation.

Promising new research suggests that men with low testosterone levels who are on testosterone replacement therapy (TRT) could have a lower risk of heart attack. To support this, Sharma et al. reported that normalization of testosterone levels through gels, patches, or injections is associated with reduced incidence of myocardial infarction (MI) and mortality among 83,010 male veterans who do not have pre-existing cardiovascular disease. [475] The study also found that men who were treated with testosterone but did not attain normal levels of the hormone did not achieve the same benefits as those whose testosterone levels did reach normal. This major study has the largest group of respondents and has the longest follow-up for testosterone replacement therapy ever conducted.

Testosterone plays a major role in the haemostatic/fibrinolytic system (system closely linked to control of inflammation). Androgens such as testosterone have anti-thrombotic action, which means that they have the ability to reduce the formation of blood clots. [476] This action can prevent the occurrence of heart attack since blood clots are the major cause of impaired blood circulation especially in the coronary artery, which supplies blood to the heart muscle. Webb et al. even reported that short-term administration of testosterone in the coronary artery induces dilation and increases coronary blood flow among 13 men with established coronary artery disease. [477]

In a meta-analysis of six short-term studies (mean, 23 weeks), Corona et al. reported that all of the studies enrolled patients with coronary heart disease who were treated with different formulations and doses of testosterone replacement therapy or placebo. [478] The results of these clinical trials showed that testosterone treatment was positively associated with a significant increase in treadmill test duration (168 seconds) and improvement in results of electrocardiogram (measures the electrical activity of the heart).

Similarly, the available studies of patients with heart failure (HF) who received testosterone replacement therapy have shown significant improvements in exercise capacity after 12 to 52 weeks of treatment. [479] The meta-analysis included four clinical trials with subjects suffering from heart failure. Researchers observed that combined results of the trials showed a significant increase in exercise capacity of almost 54 meters using the six-minute walk test after receiving testosterone replacement therapy.

A new multi-year study conducted by a team of researchers from the Intermountain Medical Center Heart Institute in Salt Lake City found that testosterone replacement therapy helped older men with abnormally low testosterone levels and pre-existing coronary artery disease reduce their risks of heart attacks, death and strokes. [480] The study also showed that patients who did not receive testosterone therapy were 80% more likely to suffer from an adverse event, suggesting that testosterone may help increase the lifespan of patients with heart disease.

Normalizes Blood Pressure

Among the many other functions of testosterone, it helps the tissues of the body to take in more blood sugar in response to insulin (hormone that helps lower blood sugar levels). In this way, blood pressure can be maintained at normal levels. Aside from this mechanism, an overwhelming body of clinical research has shown that testosterone has potent vasodilatory effect, which causes blood vessels to widen and ultimately lowers blood pressure. [481] This effect is very similar to how anti-hypertensive drugs work.     

Normal testosterone levels are known to regulate blood pressure, and a decline in this hormone could potentially cause a sudden spike in blood pressure. In fact, there are numerous studies linking low testosterone levels to blood pressure elevation. For instance, Akinloye et al. reported that there is a strong association between low blood testosterone levels and high blood pressure. [482] The researchers included patients with metabolic syndrome and type 2 diabetes. Upon checking the subjects’ testosterone levels, researchers found that their testosterone levels are abnormally low.

In one study assessing testosterone levels in both sexes, Reckelhoff et al. found that hypertensive subjects have low levels of testosterone. [483] The researchers therefore concluded that measurement of testosterone levels must be included in the medical management of hypertensive patients as well as those with medical conditions in which hypertension is a major risk factor.

Similarly, data from the population-based Study of Health in Pomerania, Germany involving 1,484 men aged 20-79 years, revealed that total testosterone were significantly lower in men with baseline and incident hypertension. [484] According to the researchers, low testosterone levels can therefore be included in the predictive markers of hypertension.

There is also increasing evidence that testosterone replacement therapy can help bring down high blood pressure. In a study by Janjgava et al., eighty-five subjects (41-65 years old) were divided into two groups: 1) a testosterone-treated group; 2) a placebo group. [485] After 6 months of treatment, subjects who were treated with testosterone undecanoate 250 mg/ml intramuscularly once every 3 months had significant reductions in their blood pressure readings compared to placebo-treated group.

In a study by Marin et al., twenty-three middle-aged abdominally obese men were treated for eight months with testosterone or with placebo. [486] After the treatment period, researchers concluded that testosterone treatment of middle-aged abdominally obese men gives beneficial effects on blood pressure and well-being, as well as cardiovascular and diabetes risk profile.

In the TIMES2 study, Jones et al. evaluated the efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS. [487] In just 6 months, researchers observed that testosterone replacement therapy was associated with beneficial effects on blood pressure.

Other high quality studies assessing the therapeutic benefits of testosterone replacement therapy in older men and postmenopausal women with high blood pressure have shown that the treatment may help lower blood pressure levels by improving blood circulation within the arteries. [488-494]

Improves Abnormal Lipid Profiles (Dyslipidemia)

Elevation in lipid profile, a blood test for abnormalities in cholesterol and triglycerides, has been consistently shown to be linked with higher incidence of deaths related to heart disease, stroke, and other serious medical conditions. Interestingly, there is growing body of clinical evidence that supports the link between low testosterone levels and elevated cholesterol levels.

A study by Wickramatilake et al. found that low levels of total testosterone in men with coronary artery disease appeared together with an abnormal lipid profile. [495] Researchers found that men with abnormally low testosterone levels have higher low density lipoprotein (bad cholesterol). In addition to this, the subjects also have lower levels of high density lipoprotein (good cholesterol).

In a similar study, Bobjer et al. found a strong link between low testosterone levels and abnormal lipid profiles. [496] The researchers therefore concluded that medical management of patients with elevated cholesterol levels must include evaluation of testosterone levels.

On the other hand, several high quality studies have shown that higher blood testosterone levels are associated with higher high density lipoprotein concentrations. In particular, it was found that two genes involved in the production of high density lipoprotein are governed by testosterone, namely, hepatic lipase (HL) and scavenger receptor B1 (SR-B1).

Because of the strong link between testosterone and cholesterol levels, a number of clinical studies has been undertaken in order to assess the therapeutic benefits of testosterone in patients with abnormal lipid profiles. For instance, a study by Huisman et al. has shown that testosterone has a beneficial effect on cholesterol and triglycerides. [497] This study also reported lower incidence of atheroma (degeneration of the arterial walls caused by accumulated fatty deposits and scar tissue) among 536 males.

In another study, Han et al. evaluated the lipid profile changes with testosterone replacement therapy in the population with testosterone deficiency syndrome. [498] After 6 months of treatment, the study participants had significant reductions in total cholesterol and triglycerides compared to baseline values. The researchers therefore concluded that testosterone has the efficacy to reduce total cholesterol and triglycerides.

In hypogonadal and elderly men, Zgliczynski et al. found that intramuscular injections of testosterone enanthate 200 mg every second week was able to normalize testosterone levels as well as reduce low density lipoprotein cholesterol levels with no side effects on the prostate and other body systems. [499] In addition, the treatment also reduced total cholesterol levels after 6 months of treatment.

Finally, because abnormal cholesterol or triglyceride levels belong to the cluster of conditions in MetS, numerous clinical trials assessing the safety and efficacy of testosterone replacement therapy in patients with MetS have shown that the treatment can significantly improve lipid profiles without any adverse side effects. [500-503] Taken together, these results suggest that testosterone does have a therapeutic benefit in individuals suffering from abnormal lipid profiles.

Treats Rheumatoid Arthritis

Inflammation is the body’s natural response to injury—but in recent years, it has also been implicated in the most feared diseases that affect humankind, including rheumatoid arthritis. As it turns out, recent clinical trials have shown a strong link between low testosterone levels and inflammation, suggesting that testosterone deficiency may increase one’s risk of developing inflammatory disorders such as rheumatoid arthritis. [504-511]

Testosterone plays a protective role in rheumatoid arthritis. To support this, Spector et al. investigated the anti-inflammatory properties of sex hormones in inflammation-induced autoimmune conditions. [512] The study revealed that testosterone can decrease aromatization (process that converts testosterone into estrogen) and increase levels of anti-inflammatory 5α-reduced androgens, suggesting that testosterone protects against the development of inflammation-induced autoimmune conditions.

Current evidence from prospective trials suggests that testosterone may help improve symptoms of arthritis. A study by Holroyd et al. revealed that testosterone supplementation among patients with rheumatoid arthritis resulted in significant improvements of symptoms as well as quality of life. [513] In addition to this, researchers observed that the treatment did not cause any adverse side effects, suggesting that testosterone is a safe and effective therapeutic option for arthritis.

A study by Cutolo et al. showed that testosterone replacement therapy may be a valuable concomitant or adjuvant treatment to be associated with other disease-modifying antirheumatic drugs in the management of patients with rheumatoid arthritis. [514] The same researchers also reported that testosterone replacement therapy in patients with rheumatoid arthritis significantly reduced the levels of IgM rheumatoid factor, a protein that is highly associated with the disease. [515]

In men with testosterone deficiency and rheumatoid arthritis, Malkin et al. observed that testosterone replacement therapy has immune-modulating properties. [516] In all of the study participants who received testosterone, a significant reduction in the levels of proinflammatory cytokines TNF-alpha and IL-1beta and an increase in anti-inflammatory cytokine IL-10 were observed.

A study by Van Vollenhoven et al. has also shown that testosterone does have a therapeutic benefit in patients with rheumatoid arthritis. [517] Improvements in symptoms as well as function of the affected body part were observed after the treatment period, suggesting that testosterone may be in par with anti-rheumatic drugs.

An overwhelming body of clinical research has also shown that aside from rheumatoid arthritis, testosterone replacement therapy may also be beneficial in patients suffering from various autoimmune and inflammatory disorders. [518-528] This suggests that testosterone may be a potential therapeutic option for these chronic, debilitating medical conditions.

Improves Sleep Quality

Many factors can alter sleeping patterns including stress, work, environment, and lifestyle. In the older population, sleep problems may actually be caused not by external factors, but rather by a natural decline in testosterone levels. Around the age of 40, men and women may begin to experience sleep disturbances which may ultimately affect their quality of life. This chronological pattern has led researchers into conducting clinical trials assessing the link between the onset of sleep disturbances and low testosterone levels.

Insufficient testosterone level has been shown to affect sleep quality. In a cohort study of men aged 65 years and over, Barrett-Connor et al. observed that those with lower testosterone levels experienced reduced sleep efficiency, increased nocturnal awakenings, and less time in slow wave sleep (one of the deepest phases of sleep). [529]

More recently, it has become clear that testosterone production is dependent on sleep. Luboshitzky et al. has shown that there is a decrease in testosterone levels in sleep-deprived individuals, especially in the older subjects, suggesting that the age-related decline in testosterone levels may trigger sleep disturbances. [530] Moreover, a recent study by Schmid et al. has also shown that restriction of sleep time to 4.5 hours was associated with a lower morning testosterone level. [531]

One of the major internal factors associated with sleep disturbances is disruption in the circadian rhythm, a roughly 24 hour cycle in the physiological processes of humans. In a study by Axelsson et al. involving night shift workers, it was found that disturbed sleep and wakefulness is associated with lower testosterone levels, suggesting that circadian rhythm disruption does have an impact on testosterone levels. [532]

On the other hand, Reynolds et al. found that healthy young men with higher blood testosterone levels have greater cognitive functioning and increased subjective sleepiness after 5 days of sleep restriction as compared to those with low blood testosterone levels. [533]This result suggests that blood testosterone levels do have an effect on sleep quality.

Because of the inverse relationship of testosterone levels and sleep quality, a number of studies have looked into the therapeutic benefits of testosterone replacement therapy on patients with sleeping difficulties. For instance, a study by Matsomoto et al. reported that intramuscular injections of testosterone enanthate 200 mg every 2 weeks in hypogonadal men with sleeping problems resulted in longer sleep time. [534]    

In another study, Shigehara et al. evaluated the effects of testosterone replacement therapy on sleep and quality of life in men with hypogonadism and nocturia (increased urination at night). [535] After 6 months of treatment, researchers observed that the participants had significant improvements in sleeping time, nocturia symptoms, and quality of life.

Promotes Fat Loss

As people age, their metabolism slows down along with testosterone production. This age-related hormonal decline leads to life-threatening abdominal obesity and increases one’s risk for a wide array of serious medical conditions. Interestingly, published studies have shown that low testosterone and obesity are strongly linked, trapping testosterone-deficient individuals in a spiral of weight gain and hormonal imbalance. [536-539]

The fact that obese men have lower blood levels of testosterone compared to lean men has been recognized for more than three decades. [540] Since then, numerous studies have consistently found a strong link between obesity and low testosterone levels in men. [541] In a group of 3219 men from the European Male Aging Study (EMAS), Tajar et al. found that obesity was associated with a 3.3-fold increased relative risk of secondary hypogonadism. [542] In a cross-sectional study of 314 Chinese men, Cao et al. similarly found that older obese men had lower blood testosterone levels compared to age-matched lean men. [543] In a cross-sectional study of 1849 community-dwelling obese U.S. American men, Dhindsa et al. found that 40% of the subjects had low testosterone levels. [544] Of note, Allan et al. reported that reductions in testosterone levels correlate with the severity of obesity. [545]

Testosterone replacement therapy may be a therapeutic option for obesity since it generates physiological levels of dihydrotestosterone (DHT), which inhibits fat cell formation. [546] In addition to this, De Maddalena et al. reported that testosterone helps regulate the balance of leptin (satiety hormone) and ghrelin (hunger hormone) in the body. [547] For these reasons, clinical and pre-clinical studies have implicated a role for testosterone in the treatment of obesity.

In a study by Saad et al., it was found that testosterone treatment reversed fat accumulation with significant improvement in lean body mass, insulin sensitivity and biochemical profiles of heart disease risk in men with testosterone deficiency. [548] Researchers observed that aside from significant improvement in body composition, testosterone treatment did not cause any adverse side effects.

In a study of 261 overweight men with testosterone deficiency, Yassin et al. reported that long-term treatment with testosterone undecanoate 1000 mg every 12 weeks for 5 years produced marked and significant decrease in body weight, waist circumference and body mass index. [549] Researchers observed that all of the study participants who received testosterone reported no adverse side effects of the treatment.

A similar study by Traish et al. found that long-term testosterone therapy in men with testosterone deficiency was associated with significant and sustained weight loss, marked reduction in waist circumference and BMI and improvement in body composition. [550] In addition to this, researchers observed that testosterone therapy improved components of the metabolic syndrome as well as quality of life of the study participants, as evidenced by increased energy utilization, increased motivation and vigor, and enhanced physical activity.

In one clinical trial, Ng Tang et al. evaluated the effects of 10-weekly intramuscular testosterone undecanoate injections in obese men with testosterone deficiency. [551] A total of 100 obese men received testosterone injections in addition to a very low energy diet (VLED) followed by 46 weeks of weight maintenance. At study end, researchers observed that the subjects had greater reductions in fat mass and in visceral fat.

Similarly, a study by Rebuffé-Scrive et al. also found that testosterone either given as a single injection (500 mg) or in moderate doses (40 mg x 4) for 6 weeks in an oral preparation, can dramatically decrease abdominal fat. [552] Researchers observed that middle-aged men who received the treatment had significant reductions in waist/hip circumference without any adverse side effects.

Other clinical trial data are also consistent in showing significant reductions in body fat mass during testosterone replacement therapy. [553-556] These results suggest that testosterone does have a beneficial effect in improving body composition by significantly reducing body fat percentage and increasing lean muscle mass in obese patients.

Reduces Wrinkles and Signs of Skin Aging

There is specific impact of sex hormones in both genders. Testosterone/estrogen ratio in men and women is one of the major factors for the gender differences in skin thickness and texture. For instance, higher levels of testosterone in men make their skin 20% thicker than female skin. [557] In addition to this, higher testosterone levels in men stimulate the oil glands to produce more sebum (oil) leading to a fatty flow and coarser skin pores. [558]

With aging, a decrease in testosterone can lead to decreased skin moisture, elasticity and thickness. Normally, testosterone is converted by an enzyme called 5-alpha reductase to DHT (dihydrotestosterone). DHT plays a crucial role in controlling sebum production. With proper sebum, the skin remains moisturized, healthy, and radiant. However, the age-related decrease in testosterone can also lead to low DHT. [559] This in turn leads to low sebum levels, which ultimately results in dry, scaly skin.

A study by Wolff et al. even confirmed that hormone replacement therapy can help reduce skin wrinkles in older women. [560] The study included 20 postmenopausal women with the same age, race, sun exposure, sunscreen use, and tobacco use. All of the study participants had been in the menopausal stage for at least five years. Nine of them received hormone replacement and the other eleven never had any hormone therapy. When assessed by a qualified plastic surgeon, postmenopausal women who received hormone replacement had more elastic skin and less severe wrinkling than women who did not receive hormone replacement therapy.

Another interesting study supports the anti-aging effect of testosterone on the skin. Glaser et al. treated two groups of women with testosterone deficiency using testosterone pellets and assessed the therapeutic benefits of the hormone therapy. [561] In study group 1, postmenopausal women were treated with subcutaneous testosterone for symptoms of androgen deficiency, four weeks after testosterone pellet insertion and upon return of symptoms of testosterone deficiency. In study group 2, twelve previously untreated postmenopausal women each received a 100 mg testosterone implant. After the study period, 50% of women reported skin improvement as evidenced by moister and softer skin, and fewer wrinkles. Moreover, the testosterone-treated groups did not report any adverse drug events, suggesting that testosterone replacement therapy is a safe and effective therapeutic option for aging skin.

Fights Hair Loss

Each hair follicle is equipped with an individual genetic code. Basically, this code is just like a “program” which determines where on the skin a hair will grow or fall out. Sex hormones such as testosterone and its even more potent metabolite, dihydrotestosterone (DHT), play an important role in the hair growth process. From birth until advanced age, these hormones work together to maintain hair quality and quantity.

Studies reported that baldness is a hormonal dysfunction, which is associated with low blood levels of testosterone. [562-564] The natural decline in testosterone causes the hair to thin, which ultimately results in baldness. In order to treat age-related hair loss, physicians prescribe testosterone replacement therapy.

The role of testosterone in hair loss is well established. A study by Glaser et al. looked at the effects of testosterone implant therapy in female patients for at least 1 year. [565] Out of the 285 patients, 76 (27%) reported thinning of hair prior to testosterone therapy. After the treatment period, 48 of these patients (63%) reported scalp hair regrowth in a high proportion without any adverse side effects.

Aside from improvement in body composition, cognition, mood, and quality of life, Bhasin et al. also reported that testosterone replacement therapy can also treat hair loss in men with testosterone deficiency. [566] In addition to improved scalp hair regrowth, researchers also observed that testosterone therapy increased hair growth in several androgen-sensitive areas (facial hair, pubic hair, and underarm hair).

Improves Quality of Life

Ultimately, patients with low testosterone have poorer scores of quality of life compared with healthy patients with normal testosterone levels for their age range. In fact, studies show that two quality of life scales, the Aging Males’ Symptoms (AMS) and the Age-Related Hormone Deficiency-Dependent Quality of Life (A-RHDQoL) scales, found that cognition, energy levels, physical capabilities, and sexual function were the factors most adversely affected by the age-related decline in testosterone levels. [567-568]

Guo et al. evaluated the safety and efficacy of testosterone replacement therapy in men with hypogonadism. [569] The researchers conducted a meta-analysis of several clinical trials focusing on the therapeutic benefits of testosterone. Their meta-analysis indicated that testosterone replacement therapy in hypogonadal men improved the quality of life, increased lean body mass and significantly decreased total cholesterol. Furthermore, testosterone treatment is well-tolerated without any adverse side effects.

Similarly, a study by Almehmadi et al. looked at the effects of long-acting intramuscular testosterone undecanoate (TU) for up to 5 years in men with late-onset hypogonadism (LOH). [570] In all, 261 patients (mean age 58 years) diagnosed with LOH received testosterone injections. As early as 3 months, health quality indicators such as the International Prostate Symptom Score (IPSS), the five-item version of the International Index of Erectile Function (IIEF-5), and the Aging Males’ Symptoms (AMS) scale significantly improved and these parameters continued to improve over the course of the trial.

Another study by Hajjar et al. found that testosterone replacement in elderly men in the form of injections at a dose of 200 mg every 2 weeks significantly increased circulating testosterone and improved quality of life of study participants without increasing their risk of prostate cancer. [571] In addition, over 84% of the subjects tolerated testosterone replacement therapy well.

A study by Kanaka et al. evaluated the effects of up to 12 intramuscular injections of testosterone enanthate 250 mg every 4 weeks in 169 men. [572] After 52 weeks, men who were given testosterone replacement therapy had significant improvement in muscle volume, voiding, physical role functioning, and sexual function, which are all indicative of improved quality of life.

In a study of men undergoing treatment with testosterone undecanoate, Yassin et al. reported that the treatment was able to improve various parameters related to quality of life including libido, vigour and vitality, sleep quality, and body composition. [573] The researchers therefore concluded that testosterone replacement therapy in hypogonadal men may be a valuable tool to restore various components of well-being.

To further assess the effects of testosterone on quality of life, Hackett et al. treated 199 men with type 2 diabetes and hypogonadism for 30 weeks with either 1,000 mg of testosterone undecanoate or matching placebo. [574] At 30 weeks and more significantly after 52 weeks, testosterone treatment improved all domains of the International Index of Erectile Function (IIEF) as well as quality of life. These positive effects were mostly observed in the testosterone-treated group compared to the placebo-treated group.

Restoring testosterone levels can make a huge difference for patients suffering from unpleasant symptoms of low testosterone. Not only does restoring testosterone level lead to a better quality of life, but better overall health too since low testosterone can lead to many other serious health conditions.

Testosterone in Athletics

Testosterone can be used to improve one’s performance. In sports, testosterone shots or creams are supposed to be magic bullets that spur athletes to run, jump, swim and to recover faster, and to become more aggressive and focused. However, it is considered to be a form of doping in most sports. [575] Anabolic steroids (including testosterone) have also been taken to build muscles, enhance strength, or endurance. They work directly by increasing the protein synthesis of the muscles, leading to large muscle fibers and enhanced repairing ability. [576]

After a series of scandals and publicity such as Ben Johnson’s improved performance at the 1988 Summer Olympics, the use of anabolic steroids were banned by many sports organizations. In 1990, the United States Congress prohibited testosterone and other anabolic steroids and were designated as a “controlled substance”, resulting in the creation of the Anabolic Steroid Control Act. [577]

Some female athletes may have naturally higher levels of the hormone testosterone than others, and may be asked by certain sports regulating body to consent to a “therapeutic proposal”, either surgery or drugs, to decrease testosterone levels to an acceptable level to compete fairly with others. [578]

History of Testosterone’s Use as an Anabolic Steroid

There is a significant difference between testosterone boosters and steroids. Testosterone boosters are consists of natural ingredients and supplements such as those from plants, [579] while steroids are synthetic substances that are created in a laboratory and are usually prescribed by doctors to treat a variety of health related issues. [580] However, the use of steroids for the purpose of muscle building or enhancing an athlete’s performance without a prescription, are actually illegal. There are two common steroids in the market: anabolic and androgenic steroids. Anabolic steroids are designed to promote muscle growth while androgenic steroids are designed to assist with sexual dysfunction such as decreased libido and erectile dysfunction. [581] Most anabolic steroids are taken orally, through a pill while others are injected.

Anabolic steroids did not receive a worldwide recognition until the 20th century but the use of pure testosterone can be traced back to the original Olympic Games. [582] Early Olympic athletes were known to ingest animal testicles before a competition to improve their performance. [583] In 1935, researchers in the Netherlands were the first to isolate a few pure milligrams of testosterone. They named the substance “testosterone” from the words testicle, sterol and the suffix of ketone. [584] Also during this year, Butenandt and Hanisch created the first synthetic version of testosterone from cholesterol. [585] It was made available to the medical community for experimentation and treatment purposes. Later, during World War II, it was found that this artificial form of testosterone can help malnourished soldiers gain weight and improve performance during combat. [586] After the war, athletes began to use steroids to have an edge over other competitors.

In the 1956 Olympics in Moscow, Soviet wrestlers performed at exceptionally high levels after using the male anabolic steroid testosterone. [587] After learning about this incident, an American physician named John Bosley Ziegler created a more selective form of what we know as anabolic steroids. [588] From that point until the early 1970’s, the use of anabolic steroids became increasingly popular among Olympic athletes and professional sports players. In 1975, the International Olympic Committee finally prohibited the use of steroids and other performance-enhancing drugs in Olympic competition. [589] However, black market sales continued to increase in the following years. In 1988, the Anti-Drug Abuse Act was introduced in order to stiffen the penalties for the sale and possession of anabolic steroids. In 1990, the United States Congress prohibited anabolic steroids and other performance-enhancing drugs, and placed certain anabolic steroids on Schedule III of the Controlled Substances Act (CSA). [590] Previously, the use of steroids was controlled only by state laws. Today, illegal sales of steroids are still prevalent among athletes, bodybuilders and even adolescents.

Effects and Side Effects of Testosterone Use

The user generally experiences an increase in muscle mass and strength very quickly. They experience heightened ability to lift heavier weights and train for more often and for longer periods of time because of their improved recovery rate. [591-592] In addition to this, testosterone use can improve mood, cognition, blood sugar levels, bone mineral density, sexual function and well-being. Large retrospective or prospective studies failed to demonstrate any serious side effects related to testosterone use. [593]

Testosterone does not cause Prostate Cancer

Recently, there has been a paradigm shift whereby testosterone replacement therapy administration in prostate cancer patients has increased. Many longitudinal studies focusing on the relationship of blood testosterone levels and subsequent risk of prostate cancer failed to find any association. [594]

In a large meta-analysis of 18 prospective studies involving 3886 men, there was no association between the risk of prostate cancer development and serum concentrations of testosterone. [595] In another study, Morgentaler et al. proposed a saturation theory which explains why testosterone does not directly cause prostate cancer. According to his model, normal prostate cells and even cancer cells seem to have a saturation point and are not affected as testosterone levels increase. [596]

In the latest meta-analysis presented in the American Urological Association 2015 Annual Meeting, Dr. Peter Boyle reported that testosterone, whether occurring naturally or taken as replacement therapy, does not cause prostate cancer or stimulate increases in the levels of prostate-specific antigen (PSA) in men. [597]

Testosterone and Cardiac Disease

Cardiovascular diseases are associated with insufficient level of the sex hormone testosterone. [598] In the largest study to date, Khaw et al. investigated the effects of testosterone levels and mortality among 11 606 healthy men aged 40 to 79 years old over a 6 to 10-year follow-up period and observed a significant association between low levels of testosterone and increased risk of cardiovascular diseases. [599]

In the most recent study, Dr. Barua, an assistant professor of medicine at the University of Kansas School of Medicine, and his colleagues reported that testosterone supplementation can reduce the risk of myocardial infarction (MI), stroke, and all-cause mortality at normal levels. [600] In hopes of providing some answers to testosterone and cardiac disease association, the study team retrospectively examined national data on 83,010 men (aged 50 and above) with documented low testosterone levels who received care from the Veteran’s Administration between 1999 and 2014. The results of the study showed that treated men with testosterone levels at normal range were 56% less likely to die during the follow-up period, 24% less likely to suffer a myocardial infarction, and 36% less likely to have a stroke.

Measuring Testosterone Levels and Route of Administration

Symptoms associated with low testosterone level may resemble other medical conditions such as thyroid problems, hormonal imbalance, side effects of medications and illegal drugs, and mental problems. To determine what’s causing these symptoms, it is recommended to schedule an appointment with your doctor for a blood test. Test to determine testosterone levels should be done in the morning between 7:00 and 10:00 am. [601] For normal results, the test should be repeated to make sure that the result is accurate. In healthy men, the levels of testosterone can change a lot from day to day, so a second test is required.

After the decision to restore testosterone levels has been made, the next step is deciding on the most effective route of administration. There are several different modes in which testosterone can be delivered, but the best method varies from person to person. A number of factors should be considered when selecting a specific testosterone modality for replacement therapy. These factors include the following: [602]

  • Acceptability of the therapy to the individual patient.
  • Effects of the therapy in general and of a particular preparation.
  • Efficacy of the treatment, which relates to the levels of the testosterone obtained.

Types of Testosterone Tests

A testosterone test or also called serum testosterone test measures the amount of testosterone in the blood. This test is ordered to determine if a person has low levels of testosterone. It is important to inform your doctor about your current medications as it may affect the result of the test. Medications that can alter testosterone test results are steroids, anticonvulsants, barbiturates, clomiphene and estrogen therapy. [603]

The levels of testosterone in the blood can be measured in terms of total, bio-available, or free testosterone and there are various tests which can be used to measure each type of testosterone:

  • Total testosterone: This test measures free, albumin-bound and Sex hormone binding globulin (SHBG) bound testosterone and is the most commonly used blood test. Total testosterone blood test is used to assess testosterone levels in patients with suspected hypogonadism.
  • Bio-available testosterone: This test measures both free and albumin-bound testosterone, both of which are available for use by cells in the body. [604]
  • Free testosterone: This test measures only the 2% of testosterone which remains unbound to proteins in the blood. [605] Free testosterone levels can also be measured through the saliva.

Types of Testosterone Therapy

The different methods of testosterone delivery are the following:

  • Intramuscular Injections: This method of testosterone delivery has been used for years because it is cost-effective and has longer duration of action. It has a 100% success rate in providing usable hormone. This method allows precise control of the dosage of testosterone administered and is considered as the most effective testosterone replacement method.
  • Implantable Testosterone: This method makes use of pellets containing 75 mg of crystalline testosterone which are implanted beneath the skin of the upper thighs, deltoid, gluteal muscles, or lower abdomen to provide slow release over 4 to 6 months.
  • Transbuccal System: It is administered through a small tablet that adheres to the gum tissue. It is slowly absorbed by the inside lining of the cheeks called buccal mucosa. Transbuccal tablets contain 30 mg of testosterone, which peaks within 30 minutes and attain steady state within 24 hours.
  • Transdermal Testosterone: This method can be applied through a patch or gel. Transdermal testosterone mimics the normal circadian rhythm of testosterone, peaking in the morning and declining to its lowest point at night. TRT gel is the most expensive of the TRT modalities but is currently the most commonly used. Testosterone gel is applied to dry skin on the abdomen, upper arm, or shoulder after bathing.
  • Oral Testosterone: Oral testosterones such as oxandrolone, danazol, fluoxynesterone, or methyltestosterone are available for clinical use. Today, testosterone undecanoate is commonly used because it is able to bypass the liver.

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