Testosterone Replacement Therapy

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The following course content

Introduction 

As low testosterone levels in men become more prevalent and the discussion around its causes, symptoms, and treatments becomes more accepted, it is important for healthcare providers to be prepared to assist patients with appropriate information and guidance. Testosterone replacement therapy (TRT) is typically the primary treatment for low testosterone (Low-T), and prescriptions for its use have risen significantly over recent years.  This course will help you delve into the risks, benefits, treatments, and the pivotal role you will play as a nurse as you educate your patients about TRT.   

Testosterone Hormone 

Over the years, testosterone has gotten a bad rap for being a source of aggression, impatience, road rage, violence, and other bad behaviors. Testosterone’s role in these things is a myth. It gets far too little attention, however, when it comes to how important it is to overall health in men and plays an important role in their health and disease processes. 

Testosterone is a sex hormone. Hormones are the body’s chemical messengers. They travel from one organ or another place in the body, usually through the bloodstream, and affect many different bodily processes. Testosterone is the major sex hormone in males. It is essential to the development of male growth and masculine characteristics. Signals sent from the brain to the pituitary gland at the base of the brain control the production of testosterone in men. The pituitary gland then relays signals to the testes to produce testosterone. A “feedback loop” regulates the number of hormones in the blood. When testosterone levels rise too high, the brain sends signals to the pituitary to reduce production. (5). 

In men, testosterone is linked to: 

1. Development of the penis and testes 
2. Deepening of the voice 
3. Growth of facial and body hair 
4. Muscle mass  
5. Muscle strength  
6. Libido (sex drive) 
7. Bone mass/density 
8. Fat distribution  
9. Red blood cell production 
10. Sperm production 

Adolescent boys with too little testosterone may not experience normal masculinization. For example, the genitals may not enlarge, facial and body hair may be scant, and the voice may not deepen normally. Testosterone may also help maintain a normal mood. There may be other important functions of this hormone that have not yet been discovered. (5) 

As mentioned before, testosterone production occurs in the testes because of receiving signals from the pituitary gland in the brain. In a condition known as primary male hypogonadism, which we will discuss later, the testes are unable to manufacture adequate amounts of testosterone regardless of the signals from a healthy pituitary gland. 

Testosterone is made by: 

1. The testicles (testis) in men where sperm is also produced 
2. The ovaries in women 
3. The adrenal glands, which rest on top of each kidney. 

Once it is released into the bloodstream, testosterone is transported by the carrier protein, sex-hormone-binding globulin. Only 1% to 2% of testosterone circulates in the blood as unbound “free” testosterone, but this fraction exhibits the most potent biological activity. (4) 

Testosterone levels vary widely depending on the age of the individual, and these values typically vary from person to person. Everyone has a different therapeutic level relative to their physiology.  

A study published by the American Urological Association in 2022 brought into question what should be considered normal levels of testosterone in men from the ages of 20-44 years of age. The purpose of the study was to determine a “normal testosterone level” for men across age brackets of five years. 

The contributors analyzed the 2011-2016 National Health and Nutrition Examination Surveys, which surveyed nationally representative samples of United States residents. Men 20 to 44 years old with testosterone levels were included. Men on hormonal medications, with a history of testicular cancer or orchiectomy, and with afternoon/evening laboratory values were excluded. They separated men into 5-year intervals and evaluated the testosterone levels of each age group, and for all men 20 to 44 years old. They used the American Urological Association definition of a “normal testosterone level” (the “middle tertile”) to calculate age-specific cutoffs for low testosterone levels. (8) 

The results were as follows: 

1. 409-558 ng/dl (20-24 years old) 
2. 413-575 ng/dl (25-29 years old) 
3. 359-498 ng/dl (30-34 years old) 
4. 352-478 ng/dl (35-39 years old) 
5. 350-473 ng/dl (40-44 years old) 

This provided a low cut-off for each 5-year age bracket which were 409, 413, 359, 352, and 350 ng/dl. 

Compared to the current accepted general value of 300 ng/dl across the entire age spectrum of men, you can see how it might be easy to miss this diagnosis and misinterpret the patient’s symptoms for another issue.  Keeping in mind these low cut-off values are averages, even more variability should be considered when discussing and evaluating testosterone labs with patients and other care providers.  

Case Study 

Part 1 

Phillip is a 38-year-old male. He has gone to see his Primary Care Provider (PCP), Dr. B. During his history and physical, Phillip tells Dr. B that he has dealt with depression his whole life. He also tells the doctor he was underweight and very thin as a boy but has gained “a lot of trunk weight” as he’s gotten older. Phillip also tells the doctor that his insomnia has been getting much worse lately and that he has trouble with concentration and irritability.  He tries to eat healthy but has a hard time getting up the energy to go to the grocery so he orders delivery more than he should. Reluctantly, he also tells the doctor that his alcohol consumption has been increasing.   

The doctor asks him if he’s taking any medications, and he says no. He has tried multiple anti-depressants in the past and they all made him feel the same, like he had no emotions at all and was very detached. Phillip continues saying he stopped taking those medications because he didn’t like feeling “dead inside” all the time. He also tells the doctor he is taking 75mg of diphenhydramine and 10mg of melatonin to sleep but still wakes up 4-5 times per night and is always exhausted.  

Dr. B. asks if he has been seeing a therapist and Phillip tells him he has not. The doctor tells him he is going to draw lab work and will follow up with him in two weeks.  In the meantime, he tells Phillip to try to get adequate rest, work on his diet, and try to get out and get some exercise.  

Phillip hands some printouts to the doctor outlining thyroid disease symptoms and low testosterone symptoms and asks the doctor if it’s possible to draw labs for these as well. Dr. B’s demeanor immediately changes, and he asks Phillip why thinks it could be these things.  

Phillip tells him that he has all the symptoms on those lists and wants to know if one of these could be the source of the problems. He continues saying his symptoms are getting worse and he doesn’t want to wind up in the hospital with something terrible.  

The doctor folds his arms and tells Phillip, “Well, I want you to know upfront that it takes three low testosterone labs in sequence to get on steroids. I’m wondering now if you’re seeking steroids.” 

Phillip is stunned by his doctor’s accusation and tells him he only wants to run the diagnostics to find out what’s going on and reminds him he hasn’t asked for any medications. He also tells the doctor that he doesn’t care what he thinks and that he wants the labs done anyway. 

The doctor angrily complies and ends the visit. 

Causes of Low Testosterone 

According to the Cleveland Clinic, Low testosterone (male hypogonadism) is a condition in which the testicles don’t produce enough testosterone and causes different symptoms at different ages (3). 

Other names for low testosterone or male hypogonadism include: 

1. Testosterone deficiency syndrome. 
2. Testosterone deficiency. 
3. Primary hypogonadism. 
4. Secondary hypogonadism. 
5. Hypergonadotropic hypogonadism. 
6. Hypogonadotropic hypogonadism. 

There are several reasons a man may suffer from low testosterone/hypogonadism. The two types are: 

1. Primary Hypogonadism (testicular disorder) 
2. Secondary Hypogonadism (pituitary/hypothalamus dysfunction) 

For the purposes of this course, we will focus on primary hypogonadism as the need for testosterone replacement therapy. 

Primary hypogonadism happens when something is wrong with the testicles that doesn’t allow them to make normal levels of testosterone. 

Another name for primary hypogonadism is hypergonadotropic hypogonadism. In this type, your pituitary gland produces more luteinizing hormones (LH) and follicle-stimulating hormone (FSH) (known as gonadotropins) in response to low testosterone levels. The high levels of these hormones would normally tell the testicles to produce more testosterone and sperm.  

However, if a man’s testicles are damaged (most commonly related to prior chemotherapy) or he is missing testicles, they can’t respond to the increased levels of gonadotropins. As a result, the testicles make too little or no testosterone and sperm. (3). 

Some possible causes of Primary Hypogonadism can include: 

1. Testicular injury 
2. Infection 
3. Orchiectomy (removal of one or both testicles) 
4. Castration 
5. Pituitary or hypothalamus issues 
6. Radiation or Chemotherapy Treatments 

The following co-morbidities can cause low testosterone in men:  

1. Hypothyroidism 
2. Congestive Heart Failure 
3. Type 2 Diabetes 
4. Obesity 
5. Chronic Obstructive Pulmonary Disorder (COPD) 
6. HIV/AIDS 
7. Chronic Opioid Use 
8. Dyslipidemia (Abnormal Lipid Levels) 
9. Hypertension 
10. Renal Failure 
11. Cardiovascular Events 

Congenital Disorders 

1. Absence of testicles at birth 
2. Undescended testicles 
3. Leydig cell hypoplasia (underdevelopment of Leydig cells in the testicles) 
4. Klinefelter’s syndrome (a genetic condition in which males are born with an extra X chromosome: XXY instead of XY). 
5. Noonan syndrome (a genetic condition that causes delayed puberty, undescended testicles, or infertility). 
6. Myotonic dystrophy (part of a group of inherited disorders called “muscular dystrophies”) (3). 

Statistical Evidence 

The American Urology Association (AUA) considers low blood testosterone to be less than 300 nanograms per deciliter (ng/dL) for adults. 

However, some researchers and healthcare providers disagree with this and feel that levels below 250 ng/dL are low. Providers also consider symptoms when diagnosing low testosterone. (3) 

Approximately 1500 men between the ages of 34 and 60 were measured for low testosterone. The results showed that approximately 24% (1 in 4) of these men had symptomatically low testosterone levels assuming a low-end value of 300 ng/dl.  

Most of these men with low testosterone levels will not come to clinical attention because testosterone levels are not routinely measured in clinical practice. For this reason, it is important to estimate prevalence based on both testosterone levels as well as clinical symptoms, which is consistent with clinical practice guidelines issued by The Endocrine Society. (2) 

Some studies suggest this number may be 30% or higher. Since the low-end value for testosterone deficiency symptoms varies from person to person, it falls on you as a nurse or other clinician to use your discernment and critical thinking skills to put together the pieces and advocate for your patients.  

This can include assessing your patient for co-morbidities which can lead to reduced testosterone levels, noting to the provider or physician the potential for the patient to need further assessment such as labs or examination, and even educating the patient and providers on the risks and problems associated with chronically low testosterone levels (2). 

Signs and Symptoms 

As noted earlier, the signs and symptoms of low testosterone can vary significantly depending on the age of your patient, their other conditions, and their general state of health.  

Low testosterone can have many symptoms and vary widely across ages and populations. Some men may not have any symptoms at all, while others may have a wide collection of them. Also, the symptoms may be milder in some cases, and severe in others.   

Some of these symptoms can include:  

1. Sleep disturbances/Insomnia 
2. Difficulty Concentrating 
3. Emotional Upset 
4. Depression 
5. Lack of motivation 
6. Mood swings 
7. In severe cases, Suicidal Ideation 
8. Low Libido 
9. Erectile Dysfunction  
10. Low Sperm Count 
11. Decrease in Muscle Size and Strength 
12. Bone Mass Loss or Osteoporosis 
13. Increase in Body Fat 

Some research even suggests an increased risk of cardiovascular incidents and cardiovascular disease. 

Low testosterone and depression have long been related, but research on this relationship is still inconclusive.  

It is important to note that there are several forms of clinical depressive disorders such as Unipolar major depression (Major Depressive Disorder), Severe Major Depression, and Persistent Depressive Disorder (Dysthymia). Only a small number of controlled clinical trials have been on men who meet the criteria for Major Depressive Disorder (MDD) as diagnosed by the DSM-5.  

The association between testosterone and MDD has yielded conflicting results with some studies suggesting an association between testosterone and MDD and others suggesting little to no association. (1) 

The action of testosterone is still greatly unknown throughout the male body and physiology, but it is evident it plays a major role in regulating functions across the entire body. Mood disturbance, lack of energy, decreased motivation, sexual dysfunction, and more can reduce the overall quality of life, and since this can be hormonally induced, traditional treatments outside hormone replacement therapy will not resolve the issues. 

The current literature that explores the effectiveness of testosterone administration for the treatment of major depression disorder and depressive symptoms is inconsistent. Testosterone can affect neurobehavioral, somatic, and metabolic pathways in humans.  

This androgen’s modulation of neurobehavior may play a role in the development of depression. In the central nervous system, testosterone has been shown to influence male arousal, behavior, energy, and mood. (20) Because of this, exogenous testosterone administration is being investigated as a potential independent or adjunctive treatment of depression. (1) 

Diagnostic Tests 

Testosterone tests measure the levels of the hormone in a person’s bloodstream, in both its bound and free forms. Some providers may also draw an additional test called a Sex Hormone Binding Globulin (SHBG) test if they think it’s necessary. This is the protein that binds free testosterone, keeping it inert until it is needed by the body. As mentioned before, usually only 1-2% of total testosterone in the body is left as “free testosterone”, and the rest is bound.  

The two main testosterone labs are: 

1. Total Testosterone, which is a measure of both free and attached testosterone. 
2. Free Testosterone, which is free testosterone only. This test can sometimes be more helpful with diagnoses.
    

These tests are usually only ordered if the patients exhibit symptoms of low testosterone, or medical conditions associated with it as well. Few providers order these tests with annual labs or as diagnostics, and as a result potential problems and diagnoses can be overlooked. 

The test itself is a simple lab draw usually consisting of one or two tubes of blood to be sent to a lab and processed.  

Testosterone Replacement Therapy 

Testosterone Replacement Therapy is the act of providing external support for a chronically low testosterone level resulting from the previously mentioned causes. The goal of this treatment is to bring a patient’s testosterone level back into a therapeutic range, reduce symptoms of low testosterone, and restore quality of life as a result.  

Although testosterone replacement therapy is the primary treatment option, some conditions that cause hypogonadism, such as obesity, can be reversible without testosterone therapy. These should be addressed before testosterone therapy is contemplated. If testosterone therapy is needed, the goals of treatment are to improve symptoms associated with testosterone deficiency and maintain sex characteristics. There are many different types of testosterone therapy. The method of treatment depends on the cause of low testosterone, the patient’s preferences, cost, tolerance, and concern about fertility (7). 

Types of Testosterone Supplements 

1. Injections, usually administered by the patient or by a doctor’s office every 1-2 weeks. 
2. Gels/Solutions, applied to the arms, shoulders, or inner thighs. These gels are subject to different absorption rates by the patient and the gel can transfer to others by skin contact. 
3. Patches adhere to the skin and can be applied to multiple sites but should be rotated to avoid skin irritation and rash.  
4. Buccal Tablets, A quick dissolve tablet placed in the pocket between the cheek and gums twice daily. It absorbs quickly but can cause gum irritation. 
5. Pellets, surgically implanted under the skin and can last from 3-6 months. These provide consistent dosages over a longer time period. The pellets can come out of the skin, infection can occur, and the dose decreases as the pellets age so symptoms of hypogonadism can recur near the end of the pellets dose period. 
6. Nasal Gel, Pumped into each nostril 3 times per day. This can result in nasal congestion and irritation. 

Benefits 

Some benefits of testosterone therapy include:  

1. Increased energy and motivation 
2. Improved mood 
3. Increased muscle mass and strength 
4. Reduced cardiovascular risk 
5. Increased concentration and focus 
6. Improved sleep patterns 
7. Improved bone strength 
8. Increased overall well-being 

Risks 

Some risks of treatment can include: 

1. Decreased sperm production 
2. Acne, specifically cystic acne 
3. Increase in prostate size 
4. Increase in red blood cell count 
5. Sleep apnea (rarely) 

Contraindications 

1. Polycythemia (high red blood cell count) 
2. Obstructive Sleep apnea 
3. Swelling in the feet or ankles 
4. Enlarged Prostate 
5. Elevated prostate-specific antigen (PSA) levels 
6. Prostate Cancer or Breast Cancer 
7. Plans for children (can result in infertility) 
8. Heart attack or stroke within the last 6 months 
9. History of or active blood clots 

The following images are courtesy of the Endocrine Society’s website and are excellent tools for information regarding testosterone treatments and their risks. 

Monitoring 

If you are treated with testosterone, your doctor will need to see you regularly, along with blood tests. Testosterone therapy is only recommended for hypogonadism patients. Boosting testosterone is NOT approved by the US Food and Drug Administration (FDA) to help improve your strength, athletic performance, physical appearance, or to treat or prevent problems associated with aging. Using testosterone for these purposes may be harmful to your health (7). 

Lab tests will be for both free and bound testosterone, sex-hormone-binding globulin, and a Prostate Specific Antigen (PSA) blood test. A complete blood count may also be ordered to monitor red blood cell counts to watch for polycythemia.

Case Study 

Part 2 

Phillip arrives at the clinic, referred to as the Low-T Clinic. Once he is taken back, a staff member takes a blood sample and tests his testosterone levels. His value comes back as 76 ng/dl.   

When the doctor comes into the room, he tells Phillip, “I can’t even imagine how awful you must feel right now. If it’s alright with you, I’m going to start treating you today.” 

Phillip replies, “Thank you so much. I don’t care what we do, I just don’t want to feel like this anymore. I’m miserable. My primary doc didn’t take this seriously.” 

The clinic doctor tells him, “Most general practitioners don’t because it doesn’t come up enough and they don’t know enough about it to make it an issue. I’m going to start you on 100mg of testosterone intramuscular once per week for six weeks. On your sixth dose, we’ll test again and see what we can do. Sound good?” 

Phillip agrees and receives his first injection at the clinic and follows up every week for the next five weeks.  

At the end of the six weeks, Phillip meets with the doctor at the clinic again and they go over his lab work. His total testosterone is now 350ng/dl, and he reports feeling somewhat better. The doctor increases his dose to 150mg intramuscular once per week for the next four weeks. Phillip agrees and receives the new dose before leaving the clinic. 

Over the next six months, Phillip and his doctor worked together to find an appropriate dose. They find that 175mg once per week intramuscular holds Phillip’s total testosterone at 725ng/dl and Phillip reports improvements in his overall well-being.  

He reports his depression is very much improved, he has more energy, his sleep is better but still erratic, and he is experiencing more stable emotions.  He and the doctor agree to keep him on this dose and monitor him.  

Patient Education 

Many patients you’ll encounter today are much more educated and savvier as they have access to a great deal of information via the internet and mobile devices. They may come to you with personal narratives that match information they have found on websites.  

Most men are unaware of the fact they may have low testosterone, and never think to ask to have tests performed or mention it to their providers. There are many resources online such as WebMD, Endocrine.org, and more.  

Educating your patients and even your providers in some cases can be invaluable when it comes to your patients’ quality of life and overall health. Knowing the symptoms, risk factors, and requesting tests can spell the difference in your patient getting the care they need and treatment.  

Resources: 

Testosterone Therapy: Potentials Benefits and Risks as you Age – Mayo Clinic 

Is Testosterone Therapy Safe? – Harvard Health 

Conclusion

Even though the research is inconclusive in some areas, there is evidence that low testosterone levels are an issue for a large portion of the population. Patients may not even know they have low testosterone, and simply attribute their symptoms to some other condition like depression, fatigue, insomnia, and a multitude of other problems.  

As a nurse, you are in a unique position to recognize these potential signs and symptoms, dig deeper into your patient’s experience, and advocate for their well-being and health by asking the providers to order the tests required to determine your patients’ testosterone levels. You may even speak with a provider seeing the patient for a psychological consult for these tests since they are in the arena of correlating with emotional disturbances.  

Keeping in mind that approximately 1 in 4 of your male patients potentially suffers from low testosterone and its symptoms, taking a moment to assess your patient and gather information can make all the difference.  

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