Testosterone Therapy Side Effects

Written by Ben Bunting: BA, PGCert. (Sport & Exercise Nutrition) // British Army Physical Training Instructor // S&C Coach

This article covers the side-effects associated with testosterone therapy (also known as TRT) and some lifestyle changes that you may wish to try first before embarking on prescription therapy.

In this article we shall cover the following:

• Testosterone
• What is TRT
• Side effects
• Alternative options
• Final note

Testosterone Levels

Before we consider testosterone therapy, let’s look at the importance of a healthy testosterone level, and also cover what testosterone is along with the benefits of testosterone.

Testosterone is an androgen hormone secreted by the Leydig cells of the testes in males. Females also secrete much smaller amounts of testosterone from their adrenal cortex and ovaries.

Testosterone is the primary male sex hormone that is responsible for male development and maturity when going through puberty as well as the reproductive glands. [1]

The male sex hormone is also responsible for male behavioral and characteristic traits such as muscle development, voice, fat levels, bone density, mood, libido and the production of sperm cells. [2]

Low levels of testosterone (hypogonadism) can negatively impact these characteristics with a reduction of muscle mass, libido and even be a risk factor for cognitive decline. [3]

As mentioned, women also naturally produce testosterone, however, this is usually around 10% less than that of a man’s production. [4]

We can measure testosterone levels from the blood which contains the total serum testosterone, but there are three parts to this which includes [5];

• Free testosterone (2-3%)
• Testosterone bound to sex hormone binding globulin (SHBG) (45%)
• Testosterone bound to other proteins (c.50%)

It is the free testosterone and testosterone bound to other proteins that is considered bioavailable and useful to increase strength, muscle and bone density. SHBG is considered too tightly bound to be bioavailable. [6]

A healthy level of serum testosterone is considered to be above 12 nmol/l. However, a consistent reading of below 8 nmol/l is considered abnormally low and that person is suffering from hypogonadism and should be treated.

The area between 8 and 12 nmol/l is when efforts should be made to improve the serum testosterone level through lifestyle changes (including dietary and physical exercise) or treatment such as testosterone therapy may be required. [7]

What does Hypogonadism mean?

This is a condition whereby the body produces very little testosterone. It can happen to men of all ages and is when the testes do not function correctly.

It is more common in older men due to the testis losing the ability to produce the required levels of testosterone, this can affect 40% of men over the age of 45, this percentage increases to 50% for men over 80. [8]

The rate in which testosterone levels decline is said to be between one and two percent every year once a man hits 30 years of age.

The gradual decline of testosterone production is often coined the ‘andropause’ and is considered to be the male equivalent of the menopause, but often goes missed due to the much more gradual show of symptoms. [9]

While the condition is becoming more recognized amongst older men, hypogonadism symptoms in young men (while entirely possible) may be acquired from acquired conditions due to lifestyle choices. These could include  illicit drug use, smoking, anabolic steroid use, or obesity as opposed to the symptoms showing in older males due to their ageing testis. [10]

Furthermore, the symptoms of hypogonadism differ between the younger and older males. You can read more about age related testosterone decline, here.

Testosterone Deficiency Symptoms

 

As already stated, the symptoms for older men are usually different to those symptoms expressed by younger males.

Symptoms for older men according to an article published in the European journal of Endocrinology are [11]:

• Fewer spontaneous erections
• Reduced libido
• Smaller testicles
• Fewer erections during sleep

Age related symptoms for younger men tend to be centred around feelings of fatigue and a lack of energy.

That said, both age groups may experience the following common symptoms related to an androgen deficiency as outlined by the Journal of Clinical Endocrinology and Metabolism [12]:

• Reduced sexual desire and activity
• Impotency
• Excessive sweating and night sweats
• Incomplete or delayed sexual development
• Lack of body hair, or less need to shave
• Low levels of fertility
• Reduced bone mass
• Less motivation
• Low mood
• Cognitive issues such as a lack of focus or memory loss
• Less muscle mass
• More body fat
• Reduced physical performance
• Poor sleep
• Increased risk of mortality
• Anaemia

Testosterone Benefits

Interest in testosterone stems back to the 1800s, a notable event in 1889 saw Charles Édouard Brown-Séquard inject himself with liquid extracted from dogs or guinea pigs who reported improvements of his physical well-being and cognitive abilities. [13]

His drastic self-experiments then appeared to encourage further interest from other scientists who wanted to understand more about the role of the testes, and how it can benefit humans. [14]

Skeletal System

Your skeleton is the framework and scaffolding that supports the body, facilitates movement, and protects your vital organs. It also produces blood cells as well as storing and releasing minerals and fat.

It consists of bones and cartilage which is then connected by ligaments. Your muscles are then connected by tendons. [15]

Testosterone plays a significant role in the maintenance and growth of bone. The standout role for testosterone is that it increases bone mineral density. This can help reduce the risk of fractures from sports or falls, it can also help prevent bone conditions such as osteoporosis which weakens the bone. [16]

Body Composition

Testosterone is well known for its effects on muscle size and strength. Numerous studies have demonstrated that increased testosterone levels can contribute towards improved strength, muscle function and mass when combined with resistance training. [17]  

Furthermore, testosterone plays a role in fat metabolism. More than one study has identified the effects that testosterone has on reducing visceral fat mass (stomach fat). [18]

Benign Prostatic Hyperplasia

This is a condition when the prostate gland becomes larger which is common in older men. This can result in pain during urination due to the flow being blocked. It can also lead to bladder, kidney or urinary tract health issues. [19]

Urinary tract issues can cause pain, such as a burning sensation when passing urine. It can also cause urine to look cloudy, make you need to urinate more often or cause pain to the lower stomach, back or under the ribs. [20] A study published in 2013 concluded that testosterone was able to reduce the symptoms associated with urinary tract health issues. [21]

Cognitive Health

Some studies have noted that those receiving testosterone treatment to enhance their levels of testosterone saw improvements in their short-term memory, which coincided with better spatial, verbal memory. [22]

Furthermore, those who were taken off from their testosterone treatment for a duration of six weeks and then restarted reported improvements of their mental health, mood, well-being, and energy. [23]

Cardiovascular Health Risk

Those who suffer from coronary heart disease combined with low testosterone are at an increased risk of death as reported by a published article from the British Medical Journal. [24]

Furthermore, it has been surmised that low levels of testosterone may also be the catalyst to developing conditions such as coronary heart disease in the first place, or even metabolic syndrome and type 2 diabetes. [25]

A review of eighteen research papers which covered more than 22,000 subjects indicated that cardiovascular mortality is related to testosterone levels. [26]

Testosterone replacement therapy has demonstrated in trials to reduce all-cause mortality, the risk of heart attack and stroke. [27]

Libido and the Reproductive System

Low levels of testosterone are related to a reduced libido. In a study of 470 men who were suffering from low levels of testosterone it was demonstrated over a one-year period that testosterone therapy in the form of a gel saw significant improvements of sexual activity and desire. [28]

Testosterone also plays an important role in male fertility. The development of sperm requires testosterone and follicle stimulating hormone to maximize fertility rates. [29]

Competitiveness, Dominance and Power

We often hear about alpha males who are born leaders, those who are super competitive in business and sport. Does testosterone have anything to do with this? Can someone with a higher level of testosterone be more dominant in a social setting than those who are suffering from hypogonadism?

According to some studies testosterone can influence our competitive and dominant behavior. However, this can be manifested in different ways such as aggressiveness or anti-social, law breaking acts or in men from the army. [30]

It has been recorded that testosterone levels are heightened before competition, such as sport, if that person is the winner, testosterone stays raised, and conversely, drops if they lose. [31]

TRT: Military Personnel and Veterans

A study published in 2006 sought to understand whether low testosterone was a risk for male veterans and found that hypogonadism was associated with an increased rate of death. [32]

Further research found that the level of testosterone therapy administration was entirely dependant on region, age and experience of the care providers meaning that the diagnosis and provision wasn't equal throughout the USA. [33]

These findings then tie in with a publsihed study of 2017 which discovered that ony 6.3% of veterans who received TRT actually had hypogonadism due to a problem with their testes or hormones. With many being merely obese of using opioids. [34]

This means that 93.7% of all veterans who received testosterone therapy were not correctly diagnosed with hypogoandism, and as such other methods to reduce their acquired symptoms should have taken place. 

What is Testosterone Replacement Therapy?

TRT is the use of synthetic testosterone that is administered to men who are suffering from hypogonadism to raise their circulating testosterone to normal levels.

This can usually be administered in the form of an injection, although patches and gels or creams are available that are applied to the skin.

Statistics show that the sales of prescribed testosterone products such as the aforementioned methods had risen in most countries between the year 2000 and 2011. These figures relate to older men who are suffering from a testosterone deficiency and fall within the clinical guidelines for use. [35]

What is Testosterone Good For?

The main role and aim of testosterone replacement therapy is to address and improve the symptoms experienced from a deficiency as previously discussed.

Even though awareness of a deficiency among medical professionals and patients alike is growing, the full benefits and risks are not absolutely clear due to the low number of studies and data available.

Additionally, thorough clinical testing of each individual is required before being prescribed with TRT, because, while some symptoms correlate with the symptoms of hypogonadism, they do not necessarily mean that low testosterone is the cause. Furthermore, being treated with TRT doesn’t always mean the issue will be resolved.  

While there is evidence that TRT can respond alleviate symptoms such as a reduced libido, impotency and sexual satisfaction, there is also contradictory evidence, data showing that the results are not consistent with ageing men. Additionally, there are potential issues regarding bias and transparency based on trials being sponsored by companies from the industry. [36]

Again, in terms of muscle mass, strength and overall body composition the findings are inconsistent or in parts, non-existent. At present we are faced with contradicting or low quality data which doesn't provide a clear-cut evaluation of the benefits associated with TRT. [37] [38]

The only exception which is supported by non-contradictory evidence is regarding the benefits for treating depression and cognitive health, however, current research, while positive, is sparse. [39]

So, we know that TRT is aimed at restoring the normal levels of testosterone which are connected to well-being, sexual function, body composition and overall quality of life. We know that while evidence at present is sparse and can be inconsistent, there is enough positive evidence to suggest that it can be beneficial for those suffering with low testosterone.

Adolescents

We must also take into account that most of the symptoms that suggest a person is hypogonadal tend to be visible in older men, whereas younger men often complain of a lack of energy and increased feelings of fatigue as outlined by Cohen, et al.

Therefore, diagnosing younger and adolescent males is more challenging. The effects of disrupted or delayed puberty can cause significant emotional distress [40] and acquired conditions that are the root cause of fatigue and other related symptoms must be investigated and if necessary, addressed using natural (evidence has demonstrated that combined iron and vitamin A is as effective as hormonal therapy) and non-invasive methods before prescribing testosterone treatments due to their potential risks.

Various studies have highlighted that rates of puberty are influenced by nutrition, obesity, eating disorders and stress. [41]

It must also be noted that delayed puberty may also be difficult to distinguish between hypogonadism, particularly when the person is at a younger age, and as such the instigation of puberty may need to be addressed before any firm diagnosis is established. [42]

Furthermore, none of the testosterone treatments that are commercially available are for use in adolescents with very little recorded use, trials or experiments available across the methods of administration which heightens the risk. [43]

Diagnosis Procedure

We have learned about the challenges clinical professionals are faced with regarding diagnosis for young males, and, equally, diagnosis for treatment for older men requires as much diligence and care.

As with younger males, other factors such as obesity, lifestyle choices or even other clinical conditions could be the cause of hypogonadal symptoms rather than low testosterone itself.

Therefore, testing to achieve a diagnosis should be given to those who have consistent symptoms, and repeated testing confirms the patient has low testosterone. [44]

Clinical Investigation

In order to ascertain whether a person has hypogonadism, a clinical professional will carry out a number of tests to understand whether TRT will be appropriate, these can include [45]:

• Blood tests (usually in the morning when testosterone levels are at their peak)
• Hormone check
• Visual field check to establish whether there are any tumors or blockages to the pituitary gland
• Scans such as an MRI

It is surmised that it is easier to diagnose, younger, leaner and healthier individuals who repeatedly throw up a low level of testosterone in tests than those suffering from chronic conditions. [46]

Testosterone Replacement Therapy Methods

There are six different treatment options, although this may vary depending on your regional healthcare provision, insurance coverage or budget.

The options available are as follows:

• Injection
• Gel
• Patch
• Transdermal solution
• Capsules
• Implant

These different methods of treatment all come with their advantages and disadvantages. For instance, an implant or injection provides a stable level of testosterone and needs less frequent replacement. However, neither should be self-administered and can cause pain and/or be invasive. 

Conversely, gels, solutions, capsules or patches can be self-administered but they may cause skin irritation, may have a short half-life, require frequent administration and potentially do not provide a stable level of testosterone. 

Side Effects and Risks of TRT

Any treatment, invasive or not needs monitoring. Different treatments may affect people differently, as no person is the same.

As we have already covered, there is not a huge wealth of data available covering a cross-sectional population who is receiving TRT.

While the benefit-to-risk ratio does appear to be positive for those otherwise healthy and fit being prescribed TRT, there is a still a lot of conflicting evidence, potential publishing bias issues and general sparse coverage of studies available which means, the user themselves are part of a wider, undeclared health experiment.

The main risks that men undertake while being administered TRT have been identified as the following [47]:

• Acne/oily skin with spots appearing on your back or chest
• Reduced fertility
• Increased risk of producing thicker blood resulting in blood clots and potential stroke
• Detection and growth of prostate cancer
• Developing breast tissue or puffy nipples
• Baldness
• Breast cancer
• Sleep apnea
• Prolonged painful erections
• Heightened aggression
• Liver function problems

However, it must be noted, that TRT is widely used and has seen many benefits for those receiving treatment such as energy levels, bone density, muscle mass and overall body composition. The risks outlined are higher for older rather than younger men. [48]

The issues that appear to affect TRT users the most include:

• Breast cancer – 11% of patients [49]
• Puffy nipples (gynecomastia) – 10-25% of patients [50]
• Thicker blood (polycythemia) – 20% of patients [51]

Monitoring for adverse effects and events should be between three and six months to minimise the risks associated with TRT.

Alternative Ways to Address Low Testosterone

We have observed from the published studies that symptoms of low testosterone can be brought upon by lifestyle choices rather than the patient suffering from hypogonadism.

It is also suggested that these acquired conditions need to be addressed first and foremost to identify whether a person needs TRT.

These can include:

• Alcohol use
• Smoking
• Exercise
• Obesity
• Illicit drug and/or steroid use
• Poor nutrition
• Sleep

Alcohol

It has been reported that excessive drinkers of alcohol suffer from a 12% testosterone deficiency compared to their non-drinking peers. [52] Further research also warrants these claims, although the direct mechanism of actions that reduce testosterone production isn’t known. [53]

If you drink often, taking a step back and reducing your intake could gain your some benefit and reduce your symptoms. 

Smoking

Research into testosterone levels regarding those who have never smoked and are not suffering from illness found that they had from 4-24% higher testosterone levels than other men. [54] However, there is data that contradicts these reports. [55]

While tobacco use is throwing up inconsistent data, it negatively effects many areas of health and reducing the amount of tobacco smoked or quitting altogether will be of benefit. 

Exercise

Physical exercise has been proven to improve many health parameters, none less than testosterone. Aerobic training for a duration of 3 months has shown to increase levels of free testosterone in overweight men - you can check out how to calculate your VO2 MAX, here to monitor your progress. [56]

A study of older versus younger men saw that whilst resistance training stimulated higher levels of circulating free and total testosterone, it was the younger men who saw greater adaptation to training. [57]

Compound exercises such as doing squats are particularly beneficial.

In addition, muscle mass, better physical performance and testosterone levels are related with findings demonstrating that testosterone affects not just the quantity but also the quality of the muscle. [58]

Weight Loss

There is a strong correlation between those with abdominal obesity (visceral fat), higher body mass index (BMI), fat percentage and waist circumference. Those with the higher waist circumferences and BMI in particular showed significantly reduced levels of testosterone. [59]

Do not take this as a reason to stop eating fats, your body needs fat for a number of physiological functions which does include testosterone regulation.

Instead, swap saturated fats found in fast foods and sweet treats for unsaturated fats contained in fish, nuts, seeds and eggs,

Illicit drugs and Steroids

Research into androgenic anabolic steroid use has discovered that those who self-administer steroids also frequently accompany this with other illicit substances that can enhance performance and appearance. Not only that, but they also often use other drugs such as opioids, cannabis, and cocaine. [60]

Long term anabolic steroid use has proven to induce hypogonadism, and treatment to reverse the effects are not always successful. [61]

Diet and Nutrition

Studies into the relationship between dietary behavior and testosterone have demonstrated a positive correlation between poor quality diet and low testosterone which can also be attributed to obesity.

High consumption of unhealthy foods such as take-away meals, pastries, dairy products and breads (normally associated with a Western diet) instead of home-cooked foods including lighter carbohydrate options and leafy greens (high in vitamin K, vitamin A, antioxidants, vitamin C and iron) are associated with a poor body composition. [62]

Improving your diet to include more vitamins and minerals such as vitamin D, zinc and boron can enhance your level of testosterone production. [63]

Including some plant extracts such as fenugreek and compounds like d-aspartic acid have demonstrated in studies to also increase free testosterone. [64]

Sleep Quality

It has been demonstrated that just one week of sleep deprivation (five hours per night) reduced testosterone levels by 10-15%. This level of sleep is commonplace among the US population with reports of 15% experiencing sleep deprivation for those who are of working age. [65]

Sleep quality and efficiency is also a marker for low testosterone. Those who experience disturbed sleep patterns with high rates of nocturnal awakenings are also associated with lower levels of testosterone. [66]

How to Naturally Fix your Testosterone Levels 

Naturally, you can induce your testosterone production in several ways. Some common examples are:

• Exercising regularly, especially weight training
• Eating a balanced diet containing protein, omega-3 fatty acids, fibers
• Enjoy adequate sleep
• Reduce a stressful lifestyle
• Spend more time doing what you like
• Have a good sexual life
• Use a natural supplement with clincially proven ingredients

Testosterone Therapy Final Note

It is widely acknowledged and established that testosterone is key for overall male health and well-being. A reduction in testosterone secretion occurs naturally as men age, however, some men may experience an accelerated loss known as hypogonadism.

There are prescription treatments available with a purported favorable benefit-to-risk ratio, however, studies are far from extensive and there are potential side-effects that could cause harm or accelerate the development of underlying health issues.

Furthermore, diagnosis can be difficult to achieve initially, and is a procedure that requires diligence and care to ascertain whether the symptoms are related to testosterone status or lifestyle choices.

If it is the latter there are safe actionable changes that can be made which can improve the persons overall health and may resolve their symptoms without the need for TRT.

Research points the way to increased activity such as concurrent training (combined aerobic and resistance training) which can improve muscle mass, bone health and aerobic fitness while reducing a persons BMI. 

A diet full of essential nutrients is also key, if this is diffuclt to acheive a recommended supplement can help but also remember to get 7-8 hours of unbroken sleep per night. 

References:

[1] Testosterone. (2018). www.sciencedirect.com. [online] Available at: https://www.sciencedirect.com/science/article/pii/B9780128012383980450 

[2] Thomas, P.G. and Fontbonne, A. (2008). Chapter 23 - Drugs and reproduction. [online] ScienceDirect. Available at: https://www.sciencedirect.com/science/article/pii/B9780702028588500257.

[3] Hormones and the Aging Brain. (2012). Handbook of Neuroendocrinology, [online] pp.573–594. Available at: https://www.sciencedirect.com/science/article/pii/B9780123750976100265 

[4] Androgens. (2008). Osteoporosis, [online] pp.1783–1792. Available at: https://www.sciencedirect.com/science/article/pii/B9780123705440500793 

[5] DUNN, J.F., NISULA, B.C. and RODBARD, D. (1981). Transport of Steroid Hormones: Binding of 21 Endogenous Steroids to Both Testosterone-Binding Globulin and Corticosteroid-Binding Globulin in Human Plasma. The Journal of Clinical Endocrinology & Metabolism, [online] 53(1), pp.58–68. Available at: https://academic.oup.com/jcem/article-abstract/53/1/58/2677560# 

‌[6] Roy, T.A., Blackman, M.R., Harman, S.M., Tobin, J.D., Schrager, M. and Metter, E.J. (2002). Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. American Journal of Physiology-Endocrinology and Metabolism, 283(2), pp.E284–E294. Available at: https://pubmed.ncbi.nlm.nih.gov/12110533/

[7] Jones, H. (2008). Testosterone for the aging male; current evidence and recommended practice. Clinical Interventions in Aging, Volume 3, pp.25–44.

[8] MULLIGAN, T., FRICK, M.F., ZURAW, Q.C., STEMHAGEN, A. and MCWHIRTER, C. (2008). Prevalence of hypogonadism in males aged at least 45 years: the HIM study. International Journal of Clinical Practice, 60(7), pp.762–769. Available online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569444

[9] Cohen, J., Nassau, D.E., Patel, P. and Ramasamy, R. (2020). Low Testosterone in Adolescents & Young Adults. Frontiers in Endocrinology, 10. Available online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966696/

[10] Duca, Y., Aversa, A., Condorelli, R.A., Calogero, A.E. and La Vignera, S. (2019). Substance Abuse and Male Hypogonadism. Journal of Clinical Medicine, [online] 8(5), p.732. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571549/

[11] Mohr, B.A., Bhasin, S., Link, C.L., O’Donnell, A.B. and McKinlay, J.B. (2006). The effect of changes in adiposity on testosterone levels in older men: longitudinal results from the Massachusetts Male Aging Study. European Journal of Endocrinology, 155(3), pp.443–452. Available online at: https://pubmed.ncbi.nlm.nih.gov/16914599/

[12] Wu, F.C.W., Tajar, A., Pye, S.R., Silman, A.J., Finn, J.D., O’Neill, T.W., Bartfai, G., Casanueva, F., Forti, G., Giwercman, A., Huhtaniemi, I.T., Kula, K., Punab, M., Boonen, S. and Vanderschueren, D. (2008). Hypothalamic-Pituitary-Testicular Axis Disruptions in Older Men Are Differentially Linked to Age and Modifiable Risk Factors: The European Male Aging Study. The Journal of Clinical Endocrinology & Metabolism, 93(7), pp.2737–2745. Available online at: https://pubmed.ncbi.nlm.nih.gov/18270261/

‌[13] C.e, B.S. (1889). NOTE ON THE EFFECTS PRODUCED ON MAN BY SUBCUTANEOUS INJECTIONS OF A LIQUID OBTAINED FROM THE TESTICLES OF ANIMALS. www.sid.ir, [online] 2(0), pp.105–107. Available at: https://www.sid.ir/en/journal/ViewPaper.aspx?ID=96101 

[14] Benedum, J. (1999). The early history of endocrine cell transplantation. Journal of Molecular Medicine, [online] 77(1), pp.30–35. Available at: https://link.springer.com/article/10.1007%2Fs001090050296 

‌[15] Andrew, W. (2019). human skeleton | Parts, Functions, Diagram, & Facts. In: Encyclopædia Britannica. [online] Available at: https://www.britannica.com/science/human-skeleton.

[16] Clarke, B.L. and Khosla, S. (2009). Androgens and bone. Steroids, 74(3), pp.296–305. Available online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679948/

[17] Kvorning, T., Christensen, L.L., Madsen, K., Nielsen, J.L., Gejl, K.D., Brixen, K. and Andersen, M. (2013). Mechanical Muscle Function and Lean Body Mass During Supervised Strength Training and Testosterone Therapy in Aging Men with Low-Normal Testosterone Levels. Journal of the American Geriatrics Society, 61(6), pp.957–962. Available online at: https://pubmed.ncbi.nlm.nih.gov/23730808/

‌[18] europepmc.org. (n.d.). Europe PMC. [online] Available at: https://europepmc.org/article/med/1335979 

[19] National Institute of Diabetes and Digestive and Kidney Diseases (2019). Prostate Enlargement (Benign Prostatic Hyperplasia) | NIDDK. [online] National Institute of Diabetes and Digestive and Kidney Diseases. Available at: https://www.niddk.nih.gov/health-information/urologic-diseases/prostate-problems/prostate-enlargement-benign-prostatic-hyperplasia.

[20] NHS Choices (2020). Urinary tract infections (UTIs). [online] NHS. Available at: https://www.nhs.uk/conditions/urinary-tract-infections-utis/.

[21] Ko, Y.H., Moon, D.G. and Moon, K.H. (2013). Testosterone Replacement Alone for Testosterone Deficiency Syndrome Improves Moderate Lower Urinary Tract Symptoms: One Year Follow-Up. The World Journal of Men’s Health, [online] 31(1), p.47. Available at: https://synapse.koreamed.org/upload/SynapseData/PDFData/2074wjmh/wjmh-31-47.pdf 

[22] Cherrier, M.M., Asthana, S., Plymate, S., Baker, L., Matsumoto, A.M., Peskind, E., Raskind, M.A., Brodkin, K., Bremner, W., Petrova, A., LaTendresse, S. and Craft, S. (2001). Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology, [online] 57(1), pp.80–88. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11445632/ 

‌[23] Wang, C., Alexander, G., Berman, N., Salehian, B., Davidson, T., McDonald, V., Steiner, B., Hull, L., Callegari, C. and Swerdloff, R.S. (1996). Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study. The Journal of Clinical Endocrinology & Metabolism, 81(10), pp.3578–3583. Available online at: https://pubmed.ncbi.nlm.nih.gov/8855804/

[24] Malkin, C.J., Pugh, P.J., Morris, P.D., Asif, S., Jones, T.H. and Channer, K.S. (2010). Low serum testosterone and increased mortality in men with coronary heart disease. Heart, 96(22), pp.1821–1825. Available online at: https://heart.bmj.com/content/96/22/1821

[25] Goodale, T., Sadhu, A., Petak, S. and Robbins, R. (2017). Testosterone and the Heart. Methodist DeBakey Cardiovascular Journal, 13(2), pp.68–72. Available online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512682/

[26] Araujo, A.B., Dixon, J.M., Suarez, E.A., Murad, M.H., Guey, L.T. and Wittert, G.A. (2011). Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. The Journal of Clinical Endocrinology and Metabolism, [online] 96(10), pp.3007–3019. Available at: https://pubmed.ncbi.nlm.nih.gov/21816776/

[27] Huynh, K. (2015). Benefit of testosterone replacement therapy on CVD and mortality. Nature Reviews Cardiology, [online] 12(10), pp.561–561. Available at: https://www.nature.com/articles/nrcardio.2015.130

‌[28] Cunningham, G.R., Stephens-Shields, A.J., Rosen, R.C., Wang, C., Bhasin, S., Matsumoto, A.M., Parsons, J.K., Gill, T.M., Molitch, M.E., Farrar, J.T., Cella, D., Barrett-Connor, E., Cauley, J.A., Cifelli, D., Crandall, J.P., Ensrud, K.E., Gallagher, L., Zeldow, B., Lewis, C.E. and Pahor, M. (2016). Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. The Journal of Clinical Endocrinology & Metabolism, 101(8), pp.3096–3104. Available online at: https://pubmed.ncbi.nlm.nih.gov/27355400/

[29] O’Donnell, L., Stanton, P. and David (2017). Endocrinology of the Male Reproductive System and Spermatogenesis. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK279031/.

[30] Giammanco, M., Tabacchi, G., Giammanco, S., Di Majo, D. and La Guardia, M. (2005). Testosterone and aggressiveness. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, [online] 11(4), pp.RA136-145. Available at: https://pubmed.ncbi.nlm.nih.gov/15795710/ 

[31] Mazur, A. and Booth, A. (1998). Testosterone and dominance in men. The Behavioral and Brain Sciences, [online] 21(3), pp.353–363; discussion 363-397. Available at: https://pubmed.ncbi.nlm.nih.gov/10097017/.

[32] jamanetwork.com. (n.d.). Low Serum Testosterone and Mortality in Male Veterans | Geriatrics | JAMA Internal Medicine | JAMA Network. [online] Available at: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/410768 

‌[33] Jasuja, G.K., Bhasin, S., Rose, A.J., Reisman, J.I., Hanlon, J.T., Miller, D.R., Morreale, A.P., Pogach, L.M., Cunningham, F.E., Park, A., Wiener, R.S., Gifford, A.L. and Berlowitz, D.R. (2017). Provider and Site-Level Determinants of Testosterone Prescribing in the Veterans Healthcare System. The Journal of Clinical Endocrinology & Metabolism, [online] 102(9), pp.3226–3233. Available at: https://academic.oup.com/jcem/article/102/9/3226/3977981 

‌[34] Jasuja, G.K., Bhasin, S., Reisman, J.I., Hanlon, J.T., Miller, D.R., Morreale, A.P., Pogach, L.M., Cunningham, F.E., Park, A., Berlowitz, D.R. and Rose, A.J. (2017). Who Gets Testosterone? Patient Characteristics Associated with Testosterone Prescribing in the Veteran Affairs System: a Cross-Sectional Study. Journal of General Internal Medicine, [online] 32(3), pp.304–311. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331013/ 

‌[35] Handelsman, D.J. (2013). Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse. Medical Journal of Australia, 199(8), pp.548–551. Available online at: https://pubmed.ncbi.nlm.nih.gov/24138381/

[36] Corona, G., Isidori, A.M., Buvat, J., Aversa, A., Rastrelli, G., Hackett, G., Rochira, V., Sforza, A., Lenzi, A., Mannucci, E. and Maggi, M. (2014). Testosterone Supplementation and Sexual Function: A Meta-Analysis Study. The Journal of Sexual Medicine, 11(6), pp.1577–1592. Available online at: https://pubmed.ncbi.nlm.nih.gov/24697970/

[37] Srinivas-Shankar, U., Roberts, S.A., Connolly, M.J., O’Connell, M.D.L., Adams, J.E., Oldham, J.A. and Wu, F.C.W. (2010). Effects of Testosterone on Muscle Strength, Physical Function, Body Composition, and Quality of Life in Intermediate-Frail and Frail Elderly Men: A Randomized, Double-Blind, Placebo-Controlled Study. The Journal of Clinical Endocrinology & Metabolism, [online] 95(2), pp.639–650. Available at: https://academic.oup.com/jcem/article/95/2/639/2596855.

[38] Storer, T.W., Woodhouse, L., Magliano, L., Singh, A.B., Dzekov, C., Dzekov, J. and Bhasin, S. (2008). Changes in Muscle Mass, Muscle Strength, and Power but Not Physical Function Are Related to Testosterone Dose in Healthy Older Men. Journal of the American Geriatrics Society, 56(11), pp.1991–1999. Available at: https://pubmed.ncbi.nlm.nih.gov/18795988/

[39] Cherrier, M.M., Matsumoto, A.M., Amory, J.K., Asthana, S., Bremner, W., Peskind, E.R., Raskind, M.A. and Craft, S. (2005). Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology, [online] 64(12), pp.2063–2068. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15985573/ 

[40] Stancampiano, M.R., Lucas-Herald, A.K., Russo, G., Rogol, A.D. and Ahmed, S.F. (2019). Testosterone Therapy in Adolescent Boys: The Need for a Structured Approach. Hormone Research in Paediatrics, [online] 92(4), pp.215–228. Available at: https://www.karger.com/Article/FullText/504670#:~:text=Testosterone%20therapy%20in%20adolescent%20boys%20is%20primarily%20aimed%20at%20increasing.

‌[41] Dwyer, A.A., Phan-Hug, F., Hauschild, M., Elowe-Gruau, E. and Pitteloud, N. (2015). TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence. European Journal of Endocrinology, [online] 173(1), pp.R15–R24. Available at: https://eje.bioscientifica.com/downloadpdf/journals/eje/173/1/R15.xml 

[42] Palmert, M.R. and Dunkel, L. (2012). Delayed Puberty. New England Journal of Medicine, 366(5), pp.443–453. Available online at: https://www.nejm.org/doi/full/10.1056/nejmcp1109290

[43] Rey, R.A. and Grinspon, R.P. (2020). Androgen Treatment in Adolescent Males With Hypogonadism. American Journal of Men’s Health, 14(3), p.155798832092244. Available online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249582/

[44] Bhasin, S., Cunningham, G.R., Hayes, F.J., Matsumoto, A.M., Snyder, P.J., Swerdloff, R.S., Montori, V.M. and Task Force, Endocrine Society (2010). Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism, [online] 95(6), pp.2536–59. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20525905 

[45] Hypogonadism and testosterone replacement therapy, Hypogonadism and testosterone replacement therapy. (2021). [online] . Available at: https://www.royalberkshire.nhs.uk/patient-information-leaflets/Endocrinology%20hypogonadism 

[46] Grossmann, M. (2011). Low Testosterone in Men with Type 2 Diabetes: Significance and Treatment. The Journal of Clinical Endocrinology & Metabolism, 96(8), pp.2341–2353. Available at: https://pubmed.ncbi.nlm.nih.gov/21646372/

‌[47] Ramasamy, R., Osterberg, Ec. and Bernie, A. (2014). Risks of testosterone replacement therapy in men. Indian Journal of Urology, [online] 30(1), p.2. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897047/.

[48] Gruenewald, D.A. and Matsumoto, A.M. (2003). Testosterone Supplementation Therapy for Older Men: Potential Benefits and Risks. Journal of the American Geriatrics Society, 51(1), pp.101–115.‌ Available at: https://pubmed.ncbi.nlm.nih.gov/12534854/

[49] Medras, M., Filus, A., Jozkow, P., Jozkow, P., Winowski, J., Sicinska-Werner, T. and Sicinska Werner, T. (2006). Breast cancer and long-term hormonal treatment of male hypogonadism. Breast Cancer Research and Treatment, [online] 96(3), pp.263–265. Available at: https://pubmed.ncbi.nlm.nih.gov/16418796/.

[50] Eckman, A. and Dobs, A. (2008). Drug-induced gynecomastia. Expert Opinion on Drug Safety, [online] 7(6), pp.691–702. Available at: https://pubmed.ncbi.nlm.nih.gov/18983216/ [Accessed 20 Apr. 2021].

[51] Drinka, P.J., Jochen, A.L., Cuisinier, M., Bloom, R., Rudman, I. and Rudman, D. (1995). Polycythemia as a Complication of Testosterone Replacement Therapy in Nursing Home Men with Low Testosterone Levels. Journal of the American Geriatrics Society, 43(8), pp.899–901. Available at: https://agsjournals.onlinelibrary.wiley.com/doi/abs/10.1111/j.1532-5415.1995.tb05534.x

‌[52]  Okwara, J.; Ezeugwunne, I.; Onunkwo, S.; Ogbodo, E.; Analike, R.; Obi-Ezeani, C.; Onuora, I.; Amah, A.; Oguaka, V.; Okezie, A. Effect of alcohol consumption on testosterone, luteinizing hormone and follicle stimulating hormone levels in males residing in Nnewi Metropolis, Anambra state, Nigeria. Ind. J. Forensic Commun. Med. 2019, 6, 13–17. Available at: https://www.semanticscholar.org/paper/Effect-of-alcohol-consumption-on-testosterone%2C-and-Ogbodo-Je/e62aafe2aba71317a7b58c06a97f15e248430a0c

[53] Nih.gov. (2020). Alcohol and the Male Reproductive System. [online] Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751073/

[54] Platz, E.A., Barber, J.R., Chadid, S., Lu, J., Dobs, A.S., Kanarek, N.F., Nelson, W.G., Bradwin, G., McGlynn, K.A. and Rohrmann, S. (2019). Nationally Representative Estimates of Serum Testosterone Concentration in Never-Smoking, Lean Men Without Aging-Associated Comorbidities. Journal of the Endocrine Society, [online] 3(10), pp.1759–1770. Available at: https://academic.oup.com/jes/article/3/10/1759/5526748 

[55] Svartberg, J., Midtby, M., Bonaa, K., Sundsfjord, J., Joakimsen, R. and Jorde, R. (2003). The associations of age, lifestyle factors and chronic disease with testosterone in men: the Tromso Study. European Journal of Endocrinology, pp.145–152. Available at: https://pubmed.ncbi.nlm.nih.gov/12887292/

‌[56] Kumagai, H., Yoshikawa, T., Zempo-Miyaki, A., Myoenzono, K., Tsujimoto, T., Tanaka, K. and Maeda, S. (2017). Vigorous Physical Activity is Associated with Regular Aerobic Exercise-Induced Increased Serum Testosterone Levels in Overweight/Obese Men. Hormone and Metabolic Research, 50(01), pp.73–79. Available at: https://pubmed.ncbi.nlm.nih.gov/28934816/

‌[57] Kraemer, W.J., Häkkinen, K., Newton, R.U., Nindl, B.C., Volek, J.S., McCormick, M., Gotshalk, L.A., Gordon, S.E., Fleck, S.J., Campbell, W.W., Putukian, M. and Evans, W.J. (1999). Effects of heavy-resistance training on hormonal response patterns in younger vs. older men. Journal of Applied Physiology, 87(3), pp.982–992. Available at: https://journals.physiology.org/doi/full/10.1152/jappl.1999.87.3.982

[58] Auyeung, T.W., Lee, J.S.W., Kwok, T., Leung, J., Ohlsson, C., Vandenput, L., Leung, P.C. and Woo, J. (2011). Testosterone but not estradiol level is positively related to muscle strength and physical performance independent of muscle mass: a cross-sectional study in 1489 older men. European Journal of Endocrinology, 164(5), pp.811–817. Available at: https://eje.bioscientifica.com/view/journals/eje/164/5/811.xml

‌[59] Ayu, A. (2019). Association of Waist-Height-Ratio, Waist Circumference, and Body Mass Index with Serum Testosterone Level in Apparently Healthy Men. Biochemistry and Molecular Biology, 4(1), p.1. Available at: http://www.sciencepublishinggroup.com/journal/paperinfo?journalid=244&doi=10.11648/j.bmb.20190401.11

‌[60] Kanayama, G. and Pope, H.G. (2012). Illicit use of androgens and other hormones. Current Opinion in Endocrinology & Diabetes and Obesity, 19(3), pp.211–219. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337343/

[61] Boregowda, K., Joels, L., Stephens, J.W. and Price, D.E. (2011). Persistent primary hypogonadism associated with anabolic steroid abuse. Fertility and Sterility, [online] 96(1), pp.e7-8. Available at: https://pubmed.ncbi.nlm.nih.gov/21575947/ 

[62] Hu, T.-Y., Chen, Y.C., Lin, P., Shih, C.-K., Bai, C.-H., Yuan, K.-C., Lee, S.-Y. and Chang, J.-S. (2018). Testosterone-Associated Dietary Pattern Predicts Low Testosterone Levels and Hypogonadism. Nutrients, [online] 10(11). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266690/.

‌[63] Pizzorno, L. (2015). Nothing Boring About Boron. Integrative medicine (Encinitas, Calif.), [online] 14(4), pp.35–48. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712861/.

[64] Wankhede, S., Mohan, V. and Thakurdesai, P. (2016). Beneficial effects of fenugreek glycoside supplementation in male subjects during resistance training: A randomized controlled pilot study. Journal of Sport and Health Science, [online] 5(2), pp.176–182. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191980/.

[65] Leproult, R. (2011). Effect of 1 Week of Sleep Restriction on Testosterone Levels in Young Healthy Men. JAMA, 305(21), p.2173. Available at: https://pubmed.ncbi.nlm.nih.gov/21632481/

[66] Barrett-Connor, E., Dam, T.-T., Stone, K., Harrison, S.L., Redline, S. and Orwoll, E. (2008). The Association of Testosterone Levels with Overall Sleep Quality, Sleep Architecture, and Sleep-Disordered Breathing. The Journal of Clinical Endocrinology and Metabolism, [online] 93(7), pp.2602–2609. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453053