Low Testosterone in Men

The usual treatment for primary and secondary hypogonadism is testosterone replacement therapy (TRT). TRT is typically recommended for patients who don't see improvement with non-pharmaceutical options mentioned earlier.

Efficacy of TRT

Summary of Evidence on Efficacy

Before delving into specific studies and meta-analyses, let's summarize the overall conclusions drawn from the body of data regarding the efficacy of TRT in patients with hypogonadism.

Overall, research on TRT suggests potential benefits for improving quality of life and sexual parameters like desire, satisfaction, and erectile function in hypogonadal patients. However, its impact on psychological symptoms, mood, and energy levels appears to be limited. While some studies indicate potential positive effects of TRT on psychological symptoms and body composition, such findings need further investigation through larger, controlled studies.

One of the largest studies in the field known as the Testosterone Trials showed positive outcomes in sexual function, bone density, anemia, walking distance, and mood, but raised concerns about increased coronary artery plaque volume, again calling for larger studies.

Several studies suggest that men with low testosterone who undergo treatment tend to live longer than untreated counterparts and we detail one of these studies below. Although there isn't robust scientific evidence supporting this, it aligns with the understanding that testosterone aids in controlling diabetes, promoting sugar clearance, and facilitating weight loss, suggesting potential health benefits beyond symptom improvement. This suggests a positive impact of testosterone on men's health, although further research is needed to establish this conclusively.

Review of Studies on TRT

An observational study of men who had low testosterone conducted by Shores and colleagues in 2012 demonstrated a decreased risk of death among those in the group who were given testosterone treatment compared with those men with low testosterone who were not treated. The data from this study are shown in the table below.

At first glance, these data might seem to suggest that testosterone treatment is essential, but it's important to approach the findings with caution. First, the study lacked randomization and one possible result is that healthier patients may have been selected to receive testosterone. In other words, it’s possible that patients who were likely to live longer regardless of treatment were included in the testosterone group.

Next, the study focused on military veterans with high levels of chronic medical conditions, making it inappropriate to generalize the conclusions to the wider population. In the words of the study authors, the study, “cannot be interpreted as showing beneficial effects of testosterone treatment or as establishing a causal relationship between testosterone treatment and reduced mortality.” Still, the results are encouraging and point to a need for larger, controlled studies.

In 2020, Diem and colleagues reviewed 58 studies including 38 randomized controlled trials and found that apart from small increases in sexual functioning and quality of life, other parameters showed little to no improvement. That said, the studies were of generally short duration (less than a year in most cases), mostly enrolled older men with a mean age of 66 years, used variable cutoffs to define low testosterone, and had varied entry criteria.

A smaller analysis by Guo and colleagues in China published in 2016 looked at 16 randomized controlled trials and found that TRT decreased a variety of aging male symptoms including psychological symptoms along with increasing lean body mass and reducing fat mass. Surprisingly, this study also found TRT contributing to a significant reduction in total cholesterol, a result which has not been borne out in other studies, although long term testosterone use has been associated with weight loss.

The Testosterone Trials (TTrials) comprised seven placebo-controlled, double-blinded trials that followed 788 men with an average age of 72 years to assess the effectiveness of TRT. The results indicated positive outcomes on a variety of metrics including sexual function, bone density and strength, anemia, walking distance and mood and depressive symptoms. The data also indicated an increase in coronary artery plaque volume in treated men, raising concerns about increased risks of cardiovascular concerns with TRT. That said, the size of the study group and the length of the treatment are not sufficient to draw definitive conclusions from the data.

The more recent TRAVERSE trial suggested that testosterone therapy was not associated with an increased risk of cardiovascular events, suggesting the treatment is safe for middle-aged men who were at risk for heart problems, although no individual study can definitively prove safety of testosterone replacement.

Forms of Testosterone Replacement Therapy

For those undergoing treatment, TRT can be administered in a variety of ways, depending on the diagnosis, availability of treatment, and preferences of the patients. Below we walk you through the different options available and the pros and cons of each.

It's important to note that the method of administering TRT can affect its effectiveness, with a tradeoff between ease of use and optimal symptom response. While patients should opt for the administration method that suits their comfort and situation best, they should also be aware of how different forms may impact their treatment.

For instance, the more convenient options like pills may seem appealing, but they often result in lower absorption rates and less consistent testosterone levels. This means they might not offer as reliable symptom improvement, however, they're also less likely to shut down natural testosterone and sperm production.

On the other hand, pellets and injectables typically provide higher and more consistent levels of testosterone, ensuring ongoing symptom relief. However, they often suppress the body's natural testosterone and sperm production more significantly than pills.

Finally, the availability of different forms of TRT can vary based on factors like where you live and your insurance coverage. To determine the best option for your needs, have a discussion with your healthcare provider. They can provide personalized guidance based on your individual circumstances.

Oral Testosterone

Testosterone undecanoate (TU) is an oral pill that is administered twice or three times daily in 40 to 80 mg doses. Due to the chemical formulation of this compound, it is absorbed in the intestines without passing through the liver. It has been in use for quite some time in Europe and other parts of the world but was only approved for use in the United States in 2022. The oral convenience of the pills along with the flexibility in terms of dosing add to their advantages over other forms, however the pills must be taken with meals, often with multiple daily doses, and absorption of the testosterone varies with the fat content of the meal, leading to fluctuations in testosterone levels. Additionally, the use of oral testosterone is contraindicated in men without structural or genetic causes of hypogonadism. Another form of testosterone, 17 alpha-methyl testosterone, is not recommended for hypogonadism treatment due to its toxic effects on the liver.

Intramuscular Testosterone

TU is also available in an injectable form and is generally administered intramuscularly in the buttocks. Dosage guidelines vary by country, with the EAU recommending 1000mg doses at week 0, followed by another 1000mg dose at week 6 and then 1000mg every 10-14 weeks. This formulation is not available in the US, where only a 750 mg injection is offered. This high-volume injection must be administered in a physician’s office in the US. The 750mg injections are given at weeks 0 and 4, and every 10 weeks thereafter.

Advantages of this format include the long-lasting effects of steady-state testosterone levels that do not fluctuate and not having to take pills multiple times each day, however sensitivity to injections including pain at the injection site and the relatively large 3 ml volume of the preparation may detract from its usefulness depending on the patient. A small percentage of patients also report coughing upon administration, an adverse reaction to the oil contained in the preparation that requires observation in a physician's office after injection. Finally, the most significant treatment-related increase in hemoglobin/ hematocrit levels is associated with injectable testosterone.

Subcutaneous Testosterone Pellets

This form of TRT involves implantation of small pellets of testosterone (standard preparations available in the United States carry 75mg of testosterone per pellet while in Europe, pellets are dosed at 200mg per pellet) into the buttocks. The AUA recommends an initial dose of 10 pellets followed by 6—12 pellets every 3 to 4 months depending on the patient’s response and the desired therapeutic level. The EAU recommends 4–6 200mg pellets about every six months. The pellets are implanted just beneath the skin of the buttocks via a small incision and release steady-state testosterone levels that do not fluctuate over the course of the ensuing months. Advantages of this format include the relatively long time periods between applications and its effectiveness in increasing testosterone levels, however it does come with the risk of infection, irritation, and occasional extrusion of one or more of the pellets.

Transdermal Patches and Gels

These patches are applied to the skin nightly and depending on geographic location, may be optimized for application either to the scrotum or to the back, abdomen, upper arms, or thighs. Doses vary with patches designed to carry anywhere from 2 to 10 mg/day. While these patches are generally easy to use and dosage adjustments are straightforward allowing for steady-state testosterone levels that do not fluctuate, they come with several drawbacks including frequently reported irritation. Additionally, patients must avoid disturbing the patch for several hours after application, including showering and swimming.

Gels provide a less irritating form of transdermal delivery and typically come in sachets, tubes and pumps delivering 5 to 50mg of testosterone per dose. The dispensed preparation is applied to the skin using an applicator or by hand. The application is simple and convenient and provides for less irritation than the patches, however some patients still report skin irritation. A major disadvantage of gels is the potential of transfer to a partner or child.

Intranasal

Intranasal testosterone is administered using a nasal spray device, with one pump delivered to each nostril every 8 hours. This convenient method allows for self-administration at home with reliable testosterone levels. While the risk of transfer is minimal, there's a potential drawback of nasal passage irritation associated with this mode of administration.

Buccal

In this mode of administration, a small tablet, patch, or gel containing testosterone is placed between the cheek and gum, allowing the testosterone to be absorbed via the mucous membranes lining these areas and transported through the blood. Although this method is convenient and allows for steady-state testosterone levels without fluctuation, some users report irritation at the site of administration as well as an unpleasant taste.

A Note About Compounded Formulations

Commercially available testosterone preparations are often preferred over those from compounding pharmacies, as commercial preparations are subject to rigorous testing, quality control, and adherence to strict regulatory standards. This ensures standardized dosing and formulation, whereas compounded preparations may lack consistency and quality control, posing potential safety risks. Opting for commercially available products offers patients greater assurance of quality, reliability, and regulatory oversight.

Monitoring TRT

After starting TRT, monitoring to ensure both efficacy and safety is crucial. Target testosterone levels in most guidelines is in the mid-normal range, typically aiming for 400-600 ng/dL. Monitoring will allow your healthcare provider to track your response to treatment, adjusting dosage as necessary to achieve optimal testosterone levels. Regular monitoring also helps identify and manage any potential side effects or complications associated with treatment. Relatively rare side effects include slight increases in irritability or unwanted energy boosts. In most cases however, patients report feeling better with normalized testosterone levels compared to lower levels.

Concerns about testosterone therapy potentially increasing the risk of cardiovascular problems, strokes, or heart attacks have also been raised over the course of the last decade or so of research, which has brought heightened scrutiny with regards to appropriate usage of TRT. Below, we highlight various aspects of TRT and its implications for specific health conditions. Each section underscores key considerations regarding TRT in relation to these conditions.

Erythrocytosis

This condition, also known as polycythemia, involves the overproduction of red blood cells. Your doctor will monitor your blood count levels, as low testosterone is associated with anemia, and receiving testosterone replacement therapy can sometimes lead to elevated blood counts. Elevated levels of red blood cells raises concerns about potential complications such as blood clots. Therefore, implementing monitoring protocols, including blood tests at baseline, at 3 to 6 months after starting treatment, and then every six to 12 months afterwards, is imperative for men undergoing testosterone therapy. Unfortunately, an unsafe level of polycythemia (high hematocrit or hemoglobin) as a risk factor for blood clots has not been defined.

Male breast cancer

Testosterone, as well as the estrogen produced through its conversion, may have a significant role in influencing breast cancer growth in men. Therefore, individuals who have been treated for male breast cancer or are currently experiencing it should avoid exposure to exogenous testosterone.

Severe Lower Urinary Tract Symptoms

Patients experiencing severe lower urinary tract symptoms are typically excluded from clinical trials, resulting in a scarcity of data regarding the long-term safety of TRT in this population. Consequently, the EAU highlights this subgroup as a matter of concern regarding TRT, however there is little data to suggest that testosterone actually worsens urinary symptoms for men with benign prostate enlargement.

Prostate Cancer

One side effect your doctor will look out for is overstimulation of the prostate gland that, although rare, is possible with TRT. While there is no evidence indicating an elevated risk of prostate cancer in hypogonadal men undergoing TRT, it's crucial to avoid testosterone treatment in men with advanced prostate cancer due to its potential to worsen the condition. Additionally, there are relatively limited long-term safety data on TRT in prostate cancer survivors, underscoring the need for heightened caution when considering TRT for men who have recovered from prostate cancer. Existing data suggest that men treated with local therapy (surgery or radiation) for prostate cancer appear to be at very low risk of recurrence of prostate cancer if they receive TRT. Depending on your age and baseline PSA levels, your doctor may perform a digital rectal examination before initiating treatment, with repeat PSA testing at regular intervals. Because Black and African American men are at increased risk of prostate cancer, these checks are especially important for early detection and monitoring of any potential abnormalities.

Cardiovascular Disease

Some studies in the early 2000’s seemed to suggest a possible link between TRT and increased risk of cardiac problems, which is why heart disease is listed as a contraindication for TRT. That said, the study populations were already at risk of heart disease and there remains no evidence indicating that TRT increases the risk of major adverse cardiovascular events. In fact, given that hypogonadism itself is linked to a higher risk of cardiovascular disease, research suggests that TRT may have either neutral or even beneficial effects in this regard, based on the observational studies showing that men with low T receiving TRT appeared to live longer than those not treated. Short term studies have shown no increase in major cardiovascular events for men receiving TRT. Long-term studies with follow-up periods extending beyond three years of treatment are currently underway to provide further insight into the safety and efficacy of TRT.

Cardiac Failure

TRT is contraindicated in men with severe chronic heart failure due to the potential risk of water retention and/or edema that can worsen the condition. Nevertheless, it's worth noting that hypogonadism is associated with a heightened risk of mortality from heart failure, underscoring the significance of ongoing randomized controlled trials investigating the effects of TRT in heart failure patients. These trials are pivotal for informing treatment decisions in this population. The EAU advises meticulous monitoring of hypogonadal men with moderate chronic cardiac failure, including regular measurements of testosterone and hematocrit.

Gynecomastia

Gynecomastia, the development of breast tissue in males, is a potential risk associated with TRT. It is associated with an imbalance of testosterone and estrogen, leading to breast tissue growth. Increased testosterone levels can result in more conversion to estrogens, allowing potential for gynecomastia. To mitigate this risk, careful monitoring of hormone levels during TRT is crucial. Adjusting testosterone dosage and incorporating medications that inhibit estrogen production, such as an aromatase inhibitor (explained later), can potentially manage this risk.

Acne

Acne is a possible side effect of TRT because of heightened oil production and alterations in skin composition. Consistent skincare, like regular cleansing and exfoliation, can alleviate symptoms. Consulting a dermatologist for topical treatments or oral medications such as antibiotics or retinoids can effectively control acne outbreaks. Adjusting TRT dosage or trying different delivery methods can also help minimize acne flare-ups.

If you're considering TRT, it's essential to approach the decision with caution and informed consent. Consult with a qualified healthcare provider who can conduct comprehensive testing, discuss potential benefits and risks, and provide personalized guidance tailored to your individual needs. Remember, while TRT may offer relief for some individuals with genuine hormonal deficiencies, it's not a panacea, and its use should be carefully considered within the context of your overall health and wellness goals.

If TRT Does Not Work for You

If symptoms persist despite several weeks of TRT, several possibilities should be considered. Initially, your doctor will reevaluate your testosterone levels and may adjust your dosage if they remain low. Certain methods of testosterone administration may be more effective at alleviating symptoms than others, so switching delivery methods, such as transitioning from pills or gels to injectables, could be explored.

Once your testosterone levels have consistently reached an optimal range for 3–6 months, if symptoms persist, it suggests they may not solely be attributable to low testosterone levels. In such cases, your doctor may discontinue TRT and explore alternative diagnoses or refer you to other specialists for further evaluation.

For individuals seeking parenthood and finding that lifestyle changes haven't alleviated symptoms, TRT isn't the primary option. In this section, we'll explore the alternative treatments available.

Why TRT Is Not An Option

First, let's discuss why TRT is not suitable for individuals trying to conceive. TRT diminishes the body's capacity to produce sperm, affecting the ability of a couple or individual to conceive.

A 2019 study conducted in Korea by Song and colleagues demonstrated noteworthy increases in sperm concentration and motility following the discontinuation of TRT for a median duration of 8 months in men from infertile couples. This study confirmed both the spermatogenic dysfunction resulting from suppression of the HPG-axis by TRT and the subsequent recovery upon cessation of TRT. The results of the study are detailed in the table below.

SERMs, Aromatase Inhibitors & Gonadotropins

If you are not a candidate for TRT due to the limitations and considerations associated with that treatment, other options are available. These therapeutic approaches offer diverse mechanisms to address hormonal imbalances and restore testosterone levels. Selective estrogen receptor modulators (SERM) like clomiphene citrate and tamoxifen citrate influence hormone production and aid in testosterone and sperm production. Aromatase inhibitors (AI) block estrogen production, while gonadotropins stimulate testosterone production. Let's delve into each of these treatment modalities and their effectiveness in managing hypogonadism.

Below we summarize how doctors often think about who should get what as well as their tradeoffs.

A 2021 systematic review by Raheem and colleagues showed that all three non-TRT treatment options resulted in statistically significant improvements in total testosterone as shown in the table below.

One important note is that these options are all used “off-label”. That is, the prescribing doctor is utilizing them for purposes outside of what they are officially approved for by regulatory agencies. Just because a medication is used off-label does not necessarily mean it is unsafe or ineffective for that particular use. It does mean, however, that there may be less research or evidence supporting its use for that specific purpose.

Selective Estrogen Receptor Modulators (SERMs)

A selective estrogen receptor modulator (SERM) is like a key that fits into different locks in the body called estrogen receptors. When a SERM fits into one lock, it acts like estrogen, making things happen as if estrogen were there. This is called an "agonist" effect. But when the same SERM fits into another lock, it stops estrogen from working there. This is called an "antagonist" effect. So, SERMs can act like estrogen in some places and block it in others, which can be helpful for treating different conditions.

In the brain, clomiphene citrate and tamoxifen citrate function as estrogen receptor antagonists. These drugs block negative feedback messages ordinarily brought about by estrogen binding, resulting in the continued release of LH and FSH from the pituitary gland. This stimulates the testes to increase both testosterone and sperm production.

Estrogen also stimulates bone growth in both men and women. Because clomiphene acts as an estrogen receptor agonist in bone tissue (acts as if it were estrogen), it has the added benefit of increasing bone mineral density which may be compromised in hypogonadal men. That said, prolonged use of SERMs has the potential to increase estrogen to undesired levels, necessitating the use of an aromatase inhibitor (discussed below).

In a study conducted in 2003, Guay and colleagues showed that after four months of treatment with CC, all 178 patients experienced significant increases in free testosterone and luteinizing hormone levels, and about 75% of participants experienced at least a partial improvement in their erections. The results of this study are summarized below.

In 2015, Mazzola and colleagues published a retrospective study of 76 men taking 25mg (n=32) or 50mg (n=17) of clomiphene every other day or 50mg daily (n=27) and found that 47 of these patients representing 67% of the study population demonstrated an increase in total testosterone levels of between 204–464 ng/dL. The outcome of this study is summarized in the table below.

Monitoring SERMs

Only a small number of men using clomiphene or tamoxifen experience side effects, as indicated by multiple studies. For instance, the study by Guay and colleagues in 2003, which involved 178 patients over a 4-month period, reported no side effects. However, other studies have identified potential side effects such as mood changes, blurred vision, breast tenderness, and weight gain.

While no definitive study has linked SERMs to blood clotting issues in men, caution is advised due to small increases in thromboembolic effects observed in women taking SERMs. Therefore, men with a history of venous thromboembolism should avoid this therapeutic approach.

Despite the known positive effects of SERMs on bone density, the EAU warns against prolonged SERM use. This is because chronic exposure to SERMs may eventually lead to downregulation of estrogen receptors in bone tissue, reducing the beneficial effects they initially provided. This downregulation can result in reduced bone density over time, predisposing individuals to osteoporosis and an increased risk of fractures. Monitoring estrogen levels is crucial and regular bone density assessments during long-term SERM therapy is recommended.

Aromatase Inhibitors

Aromatase inhibitors stop estrogen production by blocking the aromatase enzyme that converts testosterone to estradiol both in fat cells and in the testes. This leads to a similar outcome as with a SERM, increasing both LH and FSH production.

Aromatase inhibitors (AIs) are notably effective in managing hypogonadal symptoms in men with excess estrogen, particularly in alleviating low testosterone levels and gynecomastia. However, it's important to note that AIs do not directly alleviate other symptoms such as decreased libido or fatigue, which may necessitate additional interventions. Furthermore, prolonged use of aromatase inhibitors may adversely affect bone health, emphasizing the need for vigilant monitoring and personalized treatment approaches.

A 2008 study by Burnett-Bowie and colleagues randomly assigned 88 men over the age of 60 to receive either 1mg of the aromatase inhibitor anastrozole or placebo daily for 12 months. On average, total testosterone levels increased by about 50%, bioavailable testosterone levels almost doubled, and estradiol levels decreased. Although both total and bioavailable testosterone levels decreased after 12 months, they remained significantly improved and the reduction in estradiol remained steady.

It’s important to note that while this study restored testosterone levels, the decrease over time indicated a possible acquired resistance to the therapy. Additionally, impacts on sexual function, cognition, and quality of life were not measured.

Monitoring AIs

Due to their estrogen-lowering effects, AIs are linked to reduced bone mineral density and are used only sparingly for treating male hypogonadism. Some patients may experience hot flashes, weight gain and insomnia and, as for SERMs, AIs should not be used in men with a history of venous thromboembolism.

Gonadotropins

Human chorionic gonadotropin (hCG) is a protein produced by the human placenta. It shares structural and functional similarities with LH and FSH and has a longer half-life (36 hours) compared to LH (30 minutes), with a stronger binding affinity for LH receptors. In other words, hCG therapy can serve as a longer acting replacement for LH at relatively low doses, making recombinant hCG (r-hCG; a form of hCG produced in a lab) a clinically effective substitute for LH. In the clinical setting, hCG alone or in combination with recombinant FSH (r-FSH) are utilized to induce and/or maintain spermatogenesis in hypogonadal men.

A 2002 randomized, controlled study of forty men between the ages of 60–85 (mean, 67) by Liu and colleagues found that subcutaneous injections of 250 g (5000 IU) of r-hCG administered twice a week for 3 months stably increased both total and free testosterone with an accompanying increase in lean body mass while reducing fat mass, however other outcomes such as muscle strength, waist-to-hip ratio, and physical functioning remained unchanged.

In 2009, Farhat and colleagues found that gonadotropin therapy was moderately effective in achieving pregnancy in men with either congenital or acquired hypogonadism. Interestingly, they observed no disparities in outcomes based on the underlying cause of the condition. However, they identified initial testicular volume as the sole predictor of success. Subsequent investigations, such as a smaller-scale study conducted in Iraq in 2023 by Sahib and colleagues, further supported these findings, suggesting that an initial testicular volume below 5 ml adversely affected treatment outcomes.

Monitoring Gonadotropin Therapy

Gonadotropin therapy in men is typically well-tolerated with few side effects. However, it's important for patients to be aware that hCG therapy can stimulate estrogen production, potentially leading to gynecomastia. Another possible but less common side effect is an increase in hematocrit levels. Therefore, physicians strive to administer the lowest effective dosage of hCG required to stimulate testosterone production within the low-normal range (Ide, 2020). Regular monitoring of testosterone levels, PSA, and total blood counts is essential to ensure safety and efficacy throughout the treatment process.

Combination Treatment

We previously described the reduction in intratesticular testosterone concentrations and the accompanying reduction in spermatogenesis brought about by TRT. To mitigate this negative effect on spermatogenesis, ongoing studies are showing promise with combination therapy aimed at improving fertility outcomes.

In 2005, Coviello and colleagues showed that relatively low doses of hCG administered in combination with weekly T enanthate injections sustains normal intratesticular testosterone (ITT) levels in healthy men experiencing gonadotropin suppression as a result of the testosterone therapy. The impact of the hCG on ITT levels increased linearly as the dose of hCG increased. The data from this study are below.

In 2015, Wenker and colleagues showed that return of spermatogenesis was successful in 47 of 49 men who had received TRT after an average of 4.6 months on combination therapy that included hCG supplemented with either a SERM (clomiphene citrate or tamoxifen), AI (anastrozole) or rFSH, however only one participant reported a successful pregnancy.

Herbal Preparations

A 2020 study by Clemesha and colleagues at the University of Southern California Keck School of Medicine examined the most commonly incorporated ingredients in fifty “testosterone boosters” on the market. They found that most supplements lacked substantial evidence supporting their claims, with only a small percentage showing positive effects on testosterone levels. Moreover, some supplements contained components with evidence suggesting they could actually decrease testosterone levels, raising concerns about their safety and efficacy.

In 2014, Pokrywka and colleagues in Poland reviewed evidence related to Trubulus terrestris, a popular herbal supplement with claims of boosting testosterone. They highlighted the lack of evidence supporting its purported biomedical properties in humans as well as contradictory findings from existing studies that cast doubt on the marketing claims promoting it as a testosterone booster.