TRT Fundamentals

Testosterone replacement therapy (TRT) is a medical therapy intended to treat low testosterone levels in men suffering from symptoms of hypogonadism.  This guide covers the fundamentals of TRT including the basics of testosterone, low T symptoms, treatment methodology, medication formulations, side effects, common ancillary medications, and more!

What is Testosterone?

Testosterone is the principle male steroid hormone secreted by the testes.  Under the regulation of luteinizing hormone (LH), the Leydig cells in the testes synthesize and release testosterone into the bloodstream where it circulates primarily bound to two plasma proteins, sex hormone-binding globulin (SHBG) and albumin.  

SHBG has a very strong affinity to testosterone.  The SHBG-testosterone fraction in your blood serves more of a storage function and keeps the testosterone from being available for use in your body’s tissues.  Medical conditions such as hyperthyroidism, anorexia, aging, prolonged stress, and hyperestrogenic states can lead to increased levels of SHBG in the blood thereby increasing the SHBG-testosterone fraction and decreasing the amount of testosterone available for your body to use, potentially contributing the symptoms you experience.

Albumin does not bind to testosterone as strongly as SHBG, so the weakly-bound albumin-testosterone fraction is you blood is considered part of your “bioavailable testosterone”.  The American Endocrine Society practice guidelines recommend using the “free or bioavailable testosterone level” to support a diagnosis of androgen deficiency.  Therefore, you may find a clinician or practice that focuses on total and bioavailable testosterone levels only when deciding whether or not to treat you with TRT.  There is evidence that shows weakly-bound testosterone becoming available in the capillary beds but, we still aren’t sure how much of the bioavailable fraction of testosterone is available for use in these conditions.

Free testosterone is the active form of testosterone that effects body tissue directly or after conversion into estradiol or dihydrotestosterone (DHT).  Only about 2-3% of all of the testosterone released is unbound, or free, and readily available for use your body’s tissues.  Free testosterone can be measured directly using equilibrium dialysis or it can be calculated using measured total testosterone, SHBG, and albumin levels.

At Primal, we believe that the combination of total testosterone and free testosterone provide the most accurate assessment of a patient’s testosterone levels.

What are normal testosterone ranges?

Normal lab ranges are typically referred to as reference intervals or reference ranges.  These ranges are used to interpret test results, make or confirm diagnosis, and guide therapeutic interventions.  In a normal distribution the average value lies in the middle with half of the population being above the average and half of the population being below the average.  In most cases normal lab ranges cover a range of values that 95% of a healthy cohort of people fall into.  There are exceptions to this, but this is generally how testosterone ranges are reported.

trt fundamentals chart

There are different ways to create a reference range.  Some labs will refer to a reference interval study which is a type of clinical study designed to establish laboratory guidelines.  Some labs will reference “a posteriori” study which is done by evaluating lab values in existing patient databases.  Depending on the type of study and/or database used a lab will report different reference ranges.  For example, a man’s total testosterone for LabCorp is reported normal between 264-914 ng/dL and Quest Diagnostics between 250-1100 ng/dL.  Both the American Urologic Association (AUA) and American Endocrine Society (AES) recommend a total testosterone below 300 ng/dL WITH symptoms of androgen deficiency to support a diagnosis of low testosterone.

There are two major problems when using normal reference ranges and arbitrary cutoffs for diagnosing low testosterone.  The first is that these reference values and society recommendations are for all adult men.  That means a 30-year-old and a 70-year-old are assessed using the same ranges when we know definitively that their testosterone levels should be very different.  The second problem is that there is a difference between “normal” and “optimal”.

At Primal we have found that men who have symptoms of low testosterone typically feel their best without adverse effects around 850-950 ng/dL.  This isn’t a rule or a recommendation but gives you a sense of where we typically see the average optimal range.  Every member of Primal is evaluated and monitored as an individual because every man has different needs and optimal ranges.

What is low T?

Low testosterone is a combination of clinical symptoms and laboratory confirmed testosterone levels.  An average, healthy man in his 30s will have a total testosterone level in the mid-600s ng/dL and a free testosterone around 10.  As he gets older these values will decline down to a total T in the mid-low 400s and a free T less than 6 as he enters his 70s and 80s.  With these numbers in mind, we can see where the AUA and AES guidelines of a testosterone level below 300 ng/dL come from.

Figure 1

Plasma total testosterone levels by age, The Telecom Study 1985-1987

Figure 2

Mean plasma testosterone levels in healthy men

The natural decline in testosterone is important to understand because a man in his 30s should not have the testosterone levels of a man in his 70s.  The environmental assault on testosterone is leading to marked declines in T levels around the western world.  Men are experiencing symptoms of low T at younger ages as a result.  If a man in his 30s has several of the hallmark symptoms of low T and has a testosterone level of 400 ng/dL, which is low for his age, then he may benefit from the initiation of TRT.

Every situation is unique which is why it is so important to find a clinic that specializes in the intricacies of testosterone replacement and hormone optimization.

What are the symptoms of low testosterone?

Low testosterone typically manifests as a wide constellation of symptoms including:

  • Loss of sex drive (libido)
  • Erectile dysfunction
  • Fatigue
  • Difficulty maintaining or improving muscle mass
  • Diminished exercise recovery
  • Increased body fat
  • Loss of stamina
  • Difficulty concentrating
  • Depressed mood and irritability

Check Your Risk of Low T Today

A common clinical questionnaire useful for identifying patient who may be suffering from testosterone deficiency is the Androgen Deficiency in the Aging Male (ADAM) questionnaire.

Take it now for free and see if your symptoms might be related to low Testosterone

How do I know if my testosterone levels are low?

 

The only way to know if your testosterone levels are low is to do blood work.  Laboratory analysis is a critical part of any safe TRT program.  Measuring your total testosterone level, SHBG, and albumin levels and calculating your free testosterone level (cFT) is a baseline for testosterone assessment.

AUS and AES guidelines recommend two low testosterone measurements drawn prior to 10am before considering initiating treatment.  This is important because we don’t want to attribute symptoms to low testosterone that may be related to other health conditions.  As part of our intake process at Primal, we require an initial screening testosterone assessment.  

testing phase 1

After your free consultation we can order the preliminary screening lab for you.  We will also accept a total testosterone with SHBG, albumin, and cFT or a measured free T using equilibrium dialysis if you have already had it completed through a private lab or your family doctor and it has been within the past three months. 

lab testing

If your screening testosterone levels are within range to warrant TRT then we move onto a comprehensive laboratory analysis to confirm the low T levels, identify and diagnosis the cause of your low T, confirm safety parameters for TRT, and establish baselines for monitoring therapy moving forward.

How is low testosterone diagnosed?

 

Low testosterone, or hypogonadism, falls into three major diagnostic categories; primary, secondary, or mixed.

Primary hypogonadism is when the testicles are getting the appropriate signaled from the pituitary gland but aren’t responding by making more testosterone.  This can occur because of previous testicular trauma, infection, autoimmune disease, genetic condition, radiation, or surgery.

Secondary hypogonadism is when the testicles aren’t producing testosterone because they aren’t receiving the appropriate signaling from the pituitary.  This can be a problem with the pituitary gland’s release of FSH/LH or the hypothalamus’ release of GnRH.   This type of hypogonadism can occur from genetic conditions, pituitary disease, nutritional deficiency, obesity, PED use, radiation, or inflammatory diseases.

Mixed hypogonadism is a combination of the two.  This occurs when testosterone levels are low and you have variable gonadotropin levels depending on if it is predominate primary or predominate secondary.  This is the most common type of hypogonadism that we see and is the result of aging, obesity, nutritional deficiencies, and endocrine disrupting chemicals.

What is testosterone replacement therapy (TRT)?

 

For men suffering the symptoms of low testosterone who are otherwise is good health TRT is the way they feel better.  TRT is using exogenous (external), high-quality, pharmaceutical grade testosterone supplementation to increase the amount of testosterone in a man’s body to get him back to physiologic levels that alleviate or substantially reduce his symptoms.  

Medically supervised TRT focuses on keeping you “in the sweet spot” with your testosterone levels while maintaining a healthy ratio of estradiol (estrogen) and preventing or mitigating side effects of therapy.

TRT offers huge benefits for men suffering symptoms related to low levels of testosterone.  It does not make you feel like you’re back in your 20s.  It is not a panacea that will cure everything that ails you, physically, emotionally, or spiritually.  However, medically supervised TRT can provide significant enough relief of symptoms that changes in diet and exercise become possible.  It is the combination of TRT with lifestyle changes that make the most profound impact on your life.

Is there anything I can do to raise my testosterone levels naturally?

 

Absolutely.  There are a few things that can substantially raise your testosterone levels and potentially alleviate your symptoms and delay or eliminate the need for TRT.  Most of the truly useful interventions are the same interventions that will literally make every aspect of your life on this planet better.  They are also the things that require lifestyle changes that can feel impossible to do at times.

Numerous studies have shown that the higher your BMI is the lower your testosterone levels are.  Some studies have even demonstrated a greater correlation between obesity and low testosterone than with aging and low testosterone.  Testosterone is also aromatized into estradiol in fatty tissue so the more obese you are the more skewed your estrogen to testosterone levels will be which can make it harder to lose fat and contribute to gynecomastia.

Both aerobic and anaerobic exercise will help to increase testosterone levels.  Regular exercise will lead to regular pulsatile release of increased testosterone levels as well as HGH. 

Most of your natural testosterone will be released during REM sleep.  Sleep duration is an independent risk factor for low testosterone.  Even mild periods of sleep deprivation and lead to low testosterone levels.  Make time for sleep.  Plan and prepare for it.  If you have sleep apnea, get treated.

These are the endocrine disrupting chemicals (BPAs, phthalates, and organophosphates) that are so ubiquitous in the modern world.  Try to eat organic when you can.  Eat fresh instead of processed foods.  Store your food in glass, not plastic.  Don’t microwave your food in plastic storage containers.  Use metal or glass water bottles.  Wear natural fibers instead of performance clothes. Limit perfumes, candles, and fragrance sprays. The list goes on and on.  These things are everywhere.  I would recommend Shanna Swan’s book “Count Down” for a good primer.

You will also find a number of herbal remedies, foods, and vitamins that will be touted as testosterone boosters.  These will all ultimately provide only marginal gains, at best, and are unlikely to raise your testosterone levels to a point where your low T symptoms resolve.

What are my treatment options?

 

Low testosterone is an epidemic today.  Millions of American men suffer silently with the symptoms of low T for years.  Many men will never seek treatment.  However, in recent years there has been more of an awakening to the short- and long-term deleterious effects of low T and more men are starting to come out of the shadows and seek treatment.  The pharmaceutical companies have responded in kind and have developed a wider array of testosterone delivery systems to meet the unique demands of patients.  These delivery methods can be broadly classified into injectables, topicals, implantable, and orals.  At Primal we believe the optimal approach to testosterone replacement is the long practiced, tried-and-true approach of testosterone injections.  

 

Injections have been the preferred delivery method for decades.  Intramuscular or subcutaneous testosterone cypionate provides a safe and effective delivery method that allows for easy titration of medication to keep you at optimal testosterone levels to alleviate your symptoms while mitigating side effects.  They work rapidly, provide easy and accurate dosing, and cause no accidental medication exposure to loved ones.  

Topical testosterone includes a variety of transdermal delivery systems including gels, creams, and patches but we have found that gels typically work the best.  The main benefit of these systems if that there are no needles involved.  For patients that just can’t get over the idea of regular injections this is clearly a benefit.  However, it has been our experience that with proper education and training this is very rarely an insurmountable hurdle.  There are a number of significant drawbacks to topical therapies including skin irritation, difficulty making dosage adjustments, varying degrees of absorption, increased risk of hair loss, and expense.  Most importantly, there is the risk of accidently exposing loved ones through physical contact.  At Primal, we do offer topical testosterone options after careful consideration of the patient’s specific situation.  

Implantable testosterone is a crystalline formulation of testosterone delivered as pellets, about the size of a grain of rice, subcutaneously typically placed in the buttocks or abdomen.  The pellets are inserted every four months during an office surgical procedure and release testosterone over a period of 3-6 months.  With the exception of the procedure to implant the pellets there are no needles and they help with patient compliance since there is no need to do regular injections or daily topicals.  However, in our opinion the downside of pellet therapy outweighs the upside.  The procedure to implant the pellets will occur several times over the course of a year and each procedure exposes the patients to the risks of hemorrhage and infection which, in our opinion, is an unnecessary risk for regular TRT.  Furthermore, patients can experience pellet extrusion, where the pellets are actually discharged out of the patient’s body.  The biggest downside though is dosing.  There is no reliable way to predict, up front, how a patient is going to respond to a specific dose.  Implantation technique, body weight and composition, degree of physical activity, etc. all play a role in systemic absorption.  What happens when your testosterone levels at follow up are too high?  Too low?  There is no reliable way to effectively titrate the medication in between pellet insertions in order to keep the patient in the “sweet spot” through the duration of therapy.  This can lead to varying degrees of symptom control and side effects (fluid retention, mood swings, elevated estradiol, etc.).  Because of these downsides we do not prescribe or implant testosterone pellets at Primal. 

 

Oral medications include sublingual, buccal, and tablets.  Sublingual and buccal testosterone is held under the tongue or in the cheek and dissolves delivering a rapid spike in testosterone which can be accompanied by increased conversion of the testosterone into estradiol.  This rapid spike is then followed by a swift decline in levels leading to a “seesaw” or “yoyo” effect in your testosterone levels. Therefore, it is common to notice peaks and troughs in your symptoms as well.  Tablets are oral testosterone formulations that you take like any other pill. These tablets must undergo first pass metabolism through the liver which can lead to harmful effects on the liver when used over long periods of time.  Because of the peak and trough nature of these medications and long-term effects on the liver we do not prescribe oral testosterone therapy at Primal.

What are the goals/benefits of treatment?

 

The goal of TRT is to keep your testosterone levels “in the sweet spot” so the symptoms of low T that you are experiencing go away entirely or are alleviated enough to warrant ongoing therapy.  Every patient is different so there is no set “sweet spot”, but we typically find that around a total testosterone level of 850-950 ng/dL most men feel relief from their symptoms. 

A vast majority of patients are happy to have their immediate symptoms relieved with testosterone supplementation.  However, there is increasing evidence coming out in support of long-term benefits of TRT as well.  Normalization of testosterone levels is associated with a reduction in heart attack and death.  TRT can also increase bone density and improve bone strength which can mitigate development of osteopenia and osteoporosis (degrees of decreased bone density) as you get older.  Improvement in urinary stream, bladder emptying, and decreased frequency of urination has also been seen in men on TRT.

Perhaps most importantly, low testosterone levels are an independent risk factor for developing metabolic syndrome which causes a wide range on long term health complications including the risk of sudden cardiac death and cancer.  TRT has been shown to improve a number of the parameters leading to the development of this condition and improvement in health parameters for patients already diagnosed with this disease.

It is also important to understand that the goal of medically supervised TRT is not to increase testosterone to supra-physiologic levels.  This means that we don’t supplement testosterone levels above the normal range like body builders or competitive athletes using testosterone for performance enhancement do.

How long does it take to feel a difference?

 

Every patient has a unique set of circumstances that effect how quickly they will experience a response from testosterone injections.  Severity of symptoms, underlying medical conditions and medications, body fat percentage, goals of therapy, etc. all play a roll in how fast a patient will notice changes.  Most patients will notice changes within one month.  Some patients notice changes right away and some patients will have more gradual changes noticed over 2-3 months.  Typically, the first symptoms to improve are your sex drive and erections with more subtle changes in mood, energy, and sense of well-being occurring after months of treatment.  During your follow up encounters we will review your response to therapy, recheck labs, and discussing alternative treatment options if needed.

Figure 3

Testosterone effects on body composition and strength

body compostion and strength graph

Figure 4

Testosterone effects on sexual parameters

tie course on sexual parameters graph

Is it safe?

TRT is a safe and effective long-term treatment for men suffering from low testosterone.  It is important to keep in mind that TRT is a medical therapy, and as with all medical therapies there are wanted effects and unwanted effects.  However, the most frequent questions we get from members about the long-term safety of TRT aren’t about the predicable and manageable side effects of therapy but are related to misconceptions around cardiovascular disease and prostate cancer.

In January 2015, the U.S. Food and Drug Administration (FDA) issued a statement that there was a possible increased cardiovascular risk associated with testosterone use.1  Based on this conclusion they began requiring labeling for all prescription testosterone products regarding this possible increased risk of heart attack and stroke.  Needless to say, this caused widespread confusion in the medical community, as well as with patients and their families, which lingers to this day.  The data used as justification for this position was derived primarily from a study published by Vigen et al. in 20132 with a contemporaneously published study by Finkle et al. in early 20143 contributing to the media furor.  While these studies garnered major media attention, they also had critical methodological flaws.  The Vigen et al. study had so many issues that 29 international medical societies actually petitioned the Journal of the American Medical Association to retract the article!4  

In February 2015, a study by Sharma et al. was published in the European Heart Journal which evaluated TRT in 83,010 men.5  In stark juxtaposition to the previously mentioned studies this paper found that TRT was associated with a significant reduction in all cause mortality, heart attack, and stroke.  Furthermore, there are a number of studies demonstrating a marked improvement in cardiovascular disease risk factors.  Here is a good summary article providing further analysis of the literature the FDA used in their decision. (Testosterone Therapy and Cardiovascular Risk: Advances and Controversies (mayoclinicproceedings.org)) 

In response to the FDA position an international expert consensus conference was held in October 2015 to clarify the evidence about the relationship between testosterone and cardiovascular health.  This conference produced 9 unanimous resolutions including the conclusion that medical evidence does not support a link between increased cardiovascular disease and TRT.6  This is also the formal position of the American Association of Clinical Endocrinologist (AACE) and American College of Endocrinology (ACE).7

Cardiovascular disease is the leading cause of death for men in the United States8 and the preponderance of current medical literature demonstrates that testosterone replacement therapy will help you reduce your risk factors for developing disease and likely has a protective effect against heart attack and stroke.

    In 1941 the future Nobel laureate, Charles Huggins, published a paper with Clarence Hodges demonstrating that the forced suppression of testosterone levels caused regression of metastatic prostate cancer.1& lt This was a case study of a SINGLE patient.  None the less, this link between lowered testosterone levels and regression of prostate cancer was foundational to the development of androgen deprivation therapy as a treatment for prostate cancer which is an ongoing therapeutic practice today.  As with many things in medicine, this finding was also extrapolated well beyond its scientific foundation and the notion that increasing testosterone would, in fact, CAUSE prostate cancer became the prevailing medical dogma.

    Is there any evidence linking TRT to increased risk of prostate cancer?

    No.  Decades of research has failed to establish any causal link between increased testosterone levels and incidence of prostate cancer.  In 2001 Hsing reviewed 12 prospective studies evaluating the relationship between serum androgen levels and prostate cancer. 2  Only one of these studies suggested a relationship between higher testosterone levels and prostate cancer. 3  However, this conclusion was arrived at after statistical analysis performing simultaneous adjustments of four other observed hormones despite and despite no difference in the mean, highest quartile, and lowest quartile testosterone levels in the patients with prostate cancer and those in the control group.  In 2008 the Endogenous Hormones and Prostate Cancer Collaborative Group performed a meta-analysis of 18 prospective studies and found no relationship between prostate cancer risk and serum concentrations of testosterone, DHEA, or DHT. 4 Finally, in 2012 the REDUCE trial by Mullet et al. found that testosterone levels were unrelated to prostate cancer detection or severity of detectable disease. 5 Accordingly, the 2018 guidelines published by the American Urologic Association state, “clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer.” 6

    Not only does the preponderance of evidence clearly demonstrate that TRT does not increase your risk of developing prostate cancer, but a developing body of literature is actually showing that low levels of testosterone are associated with increased rates of prostate cancer and severity of disease at time of diagnosis.  According to a 2016 review by Pastuszak et al., “The link between low endogenous testosterone levels and [prostate cancer] has been extensively studied.  Men with low endogenous testosterone levels have increased rate and severe of [prostate cancer] at diagnosis, including the [metastatic disease].”7  

    Even though current evidence demonstrates that TRT will not increase your risk of developing prostate cancer, because you are a man with a prostate you may still develop disease.  Every year there are almost 250,000 new cases of prostate cancer diagnosed in the United States. 8  Any reputable TRT program you look into will screen your prostate specific antigen (PSA) levels regularly while on therapy.  Depending on your age, risk factors, and PSA levels you may also require regular prostate exams.  Increasing your testosterone levels with TRT will likely reduce your risk of developing prostate cancer and the combination of PSA screenings with prostate exams in selected patients helps to detect any evidence of cancer early so it can be treated in a timely manner.

    What are possible side effects of treatment?

    All medical therapies have risk of unwanted effects, TRT is no different. The good news is that these side effects can be largely eliminated or mitigated with good medical supervision.

    Polycythemia is the overproduction of red blood cells (RBCs).  There are two types of polycythemias: primary and secondary.  Primary polycythemia is when the overproduction of RBCs occurs because of a problem in the bone marrow.  Secondary polycythemia, also known as physiologic polycythemia, occurs as the body’s natural reaction to some other mechanism.  For example, when an athlete trains at high altitude to increase their RBCs and oxygen carrying capacity for performance enhancement. 

     

    Testosterone plays a direct role iron absorption and the stimulation of RBC production.  This leads to both higher a quantity and concentration of RBCs in the body.  This is one of the reasons that men have higher RBC levels than women.  This is also why men who have low levels of testosterone frequently have anemia, or low red blood cell levels.  When we supplement testosterone through TRT most men will see an increase in their red blood cell counts.  In some cases, this may take a man from being anemic to having normal RBCs levels.  In other cases, it may take a man from normal ranges to elevated ranges.

     

    When your RBC level becomes too high your blood starts to become thicker.  Theoretically, this increase in blood thickness can lead to blood clot formation.  Over the past several decades several studies have evaluated the association between increased blood clot risk and secondary polycythemia from all causes (altitude, lung disease, sleep apnea, et.) as well as testosterone specifically.  None of these studies have linked secondary polycythemia or TRT to an increased risk of blood clot.  According to the American Urologic Association, “clinicians should inform patients that there is no definitive evidence linking testosterone therapy to a higher incidence of venothrombolic events.”

     

    Even though secondary polycythemia associated with TRT does not increase the risk of blood clot formation, patients with very elevated blood levels may still experience unwanted symptoms such as: fatigue, headache, lightheadedness, itching, muscle pains, and burning in the hands or feet.  The most common treatment for blood levels that are too high is therapeutic phlebotomy, also known as blood donation!  This is usually done at a local donor clinic.  In some cases, decreasing the dose of testosterone or changing to a different formulation (e.g. injection to topical) may be required.

    Testosterone replacement therapy takes control of your hypothalamic-pituitary-gonadal axis.  The testosterone that you administer exogenously, through injection or topical, tells your hypothalamus that your testosterone levels are normal so less gonadotropin-releasing hormone (GnRH) gets delivered to your pituitary thus decreasing the amount of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) sent to your testicles.  FSH is the signal to make sperm and LH is the signal to make testosterone.  Just as your muscles will decrease in size if you don’t go to the gym, your testicles will decrease in size if they aren’t required to make testosterone or sperm because of the decrease in FSH and LH signaling.  Testicular atrophy affects men to varying degrees.  Some men can use high doses of steroids for performance enhancement for years and not be affected and some men experience atrophy with just enough testosterone to get them back in a normal range.  This is an aesthetic consideration and will reverse if testosterone therapy is discontinued.

    The decrease in FSH signaling means that there is a decrease in sperm production, known as spermatogenesis.  This signal reduction is so reliable that use of testosterone has actually been studied as a possible form of male birth control.  The degree to which spermatogenesis is decreased will vary between men.  If you are done having children or not interested in having children, then this typically is not a concern.  However, if you are interested in having children this is an important consideration and if you are planning to grow your family in the near future you should seriously consider delaying TRT.  There are oral medications that can be used to try and increase natural production of testosterone without shutting down spermatogenesis, but these options are not nearly as effective as testosterone supplementation directly.   Men wishing to preserve their fertility as much as possible who still want to pursue TRT should have their semen analyzed before and after the initiation of TRT.  

     

    The most common method of treating both testicular atrophy and infertility concerns is injections of human chorionic gonadotropin (hCG).  hCG mimics LH in the body and can help resist testicular atrophy and maintain a degree of normal testicular function.  Both testicular atrophy and infertility caused by TRT usually resolve after therapy has been discontinued for several months.

    The prostate is a small glad that is part of your reproductive system.  It sits just below the bladder and surrounds the urethra, the tube that allows urine to flow out of your body.  BPH is a condition in which the prostate undergoes noncancerous enlargement over time.  As the prostate grows it can also begin to encroach on the urethra leading to lower urinary tract symptoms (LUTS) such as decreased urine flow rate, increased urinary frequency, urinary hesitancy, and nocturia (waking up at night to pee).   This is an incredibly common condition as men age with 50-75% of men over 50 and 80% of men over 70 not only having BPH but also the lower urinary tract symptoms (LUTS) associated with it.1

     

    The prostate is androgen sensitive…to a point.  We know that low levels of testosterone decrease the size of the prostate generally, so men with low T commonly have smaller prostates than men with normal T levels.  When you start TRT the increase in exogenous testosterone will increase the size of your prostate, typically in the first 6 months, to an equivalent size to men whose testosterone levels are normal.  This increase is not associated with increased risk of prostate cancer and multiple studies demonstrate no increase in LUTS as a result of TRT.  In fact, studies by Haider et al2 and Shighehara et al3 have shown an improvement in LUTS for men with BPH on TRT.

    Gynecomastia is an increase in breast gland tissue in boys or men. It can be caused by a number of medications and medical conditions but is a very rare side effect of medically supervised TRT. In the setting of TRT gynecomastia is most commonly from an increase in estradiol or estradiol to testosterone ratio.

    The aromatization of testosterone into estradiol is a normal physiologic process in men. Estrogen, though found in low amounts, is crucial in preserving bone and skin health, maintaining HDL levels, increasing libido, and improving penis sensitivity. When extra testosterone is added to your system, through TRT, some men with get excessive amounts of estradiol that over time can lead to the development of gynecomastia. This is much more commonly seen in men who use anabolic steroids for performance enhancement and maintain supraphysiologic levels of testosterone for extended periods of time. Medically supervised TRT tracks estradiol levels to ensure this doesn’t become a problem.

    Gynecomastia is also seen as a result of a high estradiol to testosterone ratio. In this setting your estrogen levels are typically in the normal range, but your testosterone levels are so low that the ratio of the two is too high. Men who are not on TRT usually suffer from this type of gynecomastia.

    Gynecomastia from increased aromatization of testosterone, typically through unsupervised anabolic use, is difficult to treat and usually requires surgery to remove the tissue in order to resolve the problem. Gynecomastia from an imbalance in between your estrogen and testosterone levels can improve over time with TRT and you may not need surgery to correct it.

    In addition to the aromatization of testosterone into estradiol, testosterone is converted into dihydrotestosterone (DHT). DHT is an extremely powerful and important hormone but is also responsible for increasing the oil production in your skin. The increased oil production can lead to increased acne in some patients. Good hygiene and increasing your injection schedule to more than once per week is usually sufficient to manage this. Using specific anti-acne soaps, zinc, and vitamin D can also help. Finally, there are prescription medications like isotretinoin (Accutane) and antibiotics that can be used as a last resort.
    Androgenetic alopecia, or male balding, is a complex multifactorial issue with strong genetic component. If you look at your father, grandfathers, and great grandfathers and see lots of bald men, then the chances are you’re going to lose your hair. The speed at which that happens varies depending on your genetics, but generally speaking by the time most men are feeling the symptoms of low testosterone they are already experiencing hair loss if they have the genetic predisposition. While scalp health and blood flow certainly contribute to hair loss, the primary factor seems to be the genetic sensitivity of your hair follicles to DHT, a product of testosterone metabolism. TRT will increase your testosterone levels and subsequently your levels of DHT. Topical preparations tend to have higher conversion than injectable. The increase in DHT will likely cause the genetically predisposed patient to experience hair loss, which would occur regardless, at a slightly faster rate. This rate can range wildly and there is no way to know exactly what it will be for you. If you are genetically predisposed to hair loss and your goal is to preserve your hair as long as possible, then you should consider delaying TRT initiation. Once the impact of your low T symptoms affects your life greater than the impact of possibly losing your hair at a faster rate, then pursue treatment. If you do not have the genetic predisposition towards baldness, then TRT is unlikely to cause hair loss.
    Cholesterol is an organic molecule biosynthesized in your body and an essential part of every cell. It makes the cell membranes, participates in cellular signaling and nerve conduction, and is a precursor to steroid and vitamin D synthesis. Cholesterol is typically measured by looking at lipoproteins which are a combination of lipids and the proteins they are connected to that allows them to circulate in the blood stream. These are historically measured as HDL and LDL, high density lipoproteins and low-density lipoproteins. HDL is traditionally characterized as “good” cholesterol and “LDL” as bad cholesterol.

    Lowered HDL levels have been seen with oral nonaromatizable steroids and supraphysiologic dosing of testosterone up to 600mg per week1, well outside the practice of TRT therapy. However, several studies show no change in serum lipid profiles in patients on physiologic replacement doses of testosterone. Whitsel et al2 performed a meta-analysis of 19 studies that evaluated serum lipids and testosterone and found a vast majority demonstrated neutral effect on lipid profiles.

    Obstructive sleep apnea (OSA) is a common chronic sleep disorder characterized by complete or partial upper airway obstruction which results in oxygen desaturation and sleep fragmentation. Risk factors for OSA include family history of OSA or snoring, large neck circumference, and obesity. Symptoms include loud snoring, frequent waking, gasping for air during sleep, and excessive daytime sleepiness. OSA is diagnosed with a sleep study and typically treated with a CPAP machine though for mild sleep apnea oral appliances are also an option.

    The development or worsening of already existing OSA with TRT is an ongoing area of research. The initial studies linking TRT to OSA were small and generally found in men who had other identifiable risk factors for OSA.1 Subsequent studies evaluating slightly larger cohorts offered mixed results with evidence that changes in nocturnal breathing patterns resolving within 18 weeks of therapy intiaion.2-4 Most recently, a study by Cole et al. looking at 3,422 male US service members did find a 2-year risk of OSA in the TRT cohort of 16.5% compared to non-TRT cohort of 12.7%.5

    The evidence we have to date does suggest that this is a very uncommon occurrence. When starting a TRT program your provider should ask you about symptoms of OSA and monitor these symptoms during therapy with referral for a sleep study if you develop symptoms of OSA. If you do develop OSA while on TRT the evidence also shows that these symptoms will resolve if discontinuing therapy.

    The goal of medically supervised TRT is to maximize the wanted effects while mitigating or negating entirely the unwanted effects.  What makes medically supervised TRT safe and effective is a thorough medical evaluation, review of your medical history, regular laboratory reassessments, appropriate treatment plans, ongoing clinical monitoring, and patient education.

    How do I get started?

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    Text Citations

    Citations
    Cardiovascular Risk
    1. Center for Drug Evaluation and Research. (2014, January 31). FDA drug Safety Communication: FDA cautions about using TESTOSTERONE products for low Testosterone due to Aging; requires Labeling change to inform of possible increased risk of heart attack and stroke with use. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due. 
    2. Vigen, R. (2013). Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 310(17), 1829. https://doi.org/10.1001/jama.2013.280386 
    3. Finkle, W. D., Greenland, S., Ridgeway, G. K., Adams, J. L., Frasco, M. A., Cook, M. B., Fraumeni, J. F., & Hoover, R. N. (2014). Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE, 9(1). https://doi.org/10.1371/journal.pone.0085805 
    4. Morgentaler, A., Miner, M. M., Caliber, M., Guay, A. T., Khera, M., & Traish, A. M. (2015). Testosterone therapy and cardiovascular risk: Advances and controversies. Mayo Clinic Proceedings, 90(2), 224–251. https://doi.org/10.1016/j.mayocp.2014.10.011 
    5. Sharma, R., Oni, O. A., Gupta, K., Chen, G., Sharma, M., Dawn, B., Sharma, R., Parashara, D., Savin, V. J., Ambrose, J. A., & Barua, R. S. (2015). Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. European Heart Journal, 36(40), 2706–2715. https://doi.org/10.1093/eurheartj/ehv346 
    6. Morgentaler, A., Zitzmann, M., Traish, A. M., Fox, A. W., Jones, T. H., Maggi, M., Arver, S., Aversa, A., Chan, J. C. N., Dobs, A. S., Hackett, G. I., Hellstrom, W. J., Lim, P., Lunenfeld, B., Mskhalaya, G., Schulman, C. C., & Torres, L. O. (2016). Fundamental concepts regarding testosterone deficiency and treatment. Mayo Clinic Proceedings, 91(7), 881–896. https://doi.org/10.1016/j.mayocp.2016.04.007 
    7. Goodman, N., Guay, A., Dandona, P., Dhindsa, S., Faiman, C., & Cunningham, G. R. (2015). American Association of CLINICAL endocrinologists and American College of Endocrinology position statement on the Association of testosterone and cardiovascular risk. Endocrine Practice, 21(9), 1066–1073. https://doi.org/10.4158/ep14434.ps
    8. Centers for Disease Control and Prevention. (2020, September 8). Heart Disease Facts. Centers for Disease Control and Prevention. https://www.cdc.gov/heartdisease/facts.htm.
    Prostate Cancer
    1. Huggins, C., & Hodges, C. V. (2002). Studies on Prostatic CANCER: I. the effect of CASTRATION, of estrogen and of ANDROGEN injection ON Serum Phosphatases in Metastatic carcinoma of the prostate. Journal of Urology, 168(1), 9–12. https://doi.org/10.1016/s0022-5347(05)64820-3 
    2. Hsing, A. W. (2001). Hormones and prostate cancer: What’s next? Epidemiologic Reviews, 23(1), 42–58. https://doi.org/10.1093/oxfordjournals.epirev.a000795 
    3. Gann, P. H., Hennekens, C. H., Ma, J., Longcope, C., & Stampfer, M. J. (1996). Prospective study of sex hormone levels and risk of prostate cancer. JNCI Journal of the National Cancer Institute, 88(16), 1118–1126. https://doi.org/10.1093/jnci/88.16.1118 
    4. Hormones, E. (2008). Endogenous sex hormones and prostate Cancer: A collaborative analysis of 18 prospective studies. JNCI: Journal of the National Cancer Institute, 100(3), 170–183. https://doi.org/10.1093/jnci/djm323 
    5. Muller, R. L., Gerber, L., Moreira, D. M., Andriole, G., Castro-Santamaria, R., & Freedland, S. J. (2012). Serum testosterone and DIHYDROTESTOSTERONE and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate Cancer events trial. European Urology, 62(5), 757–764. https://doi.org/10.1016/j.eururo.2012.05.025 
    6. Mulhall JP, Trost LW, Brannigan RE et al: Evaluation and management of testosterone deficiency: AUA guideline. J Urol 2018; 200: 423.
    7. Pastuszak, A. W., Rodriguez, K. M., Nguyen, T. M., & Khera, M. (2016). Testosterone therapy and prostate cancer. Translational Andrology and Urology, 5(6), 909–920. https://doi.org/10.21037/tau.2016.08.17 
    8. Key statistics for prostate cancer: Prostate cancer facts. American Cancer Society. (2021, February 13). https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html. 
    Benign Prostatic Hypertrophy (BPH)
    1. Egan, K. B. (2016). The epidemiology of benign prostatic hyperplasia associated with lower urinary tract symptoms. Urologic Clinics of North America, 43(3), 289–297. https://doi.org/10.1016/j.ucl.2016.04.001 
    2. Haider, A., Gooren, L. J., Padungtod, P., & Saad, F. (2009). Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia, 41(1), 7–13. https://doi.org/10.1111/j.1439-0272.2008.00880.x 
    3. Shigehara, K., Sugimoto, K., Konaka, H., Iijima, M., Fukushima, M., Maeda, Y., Mizokami, A., Koh, E., Origasa, H., Iwamoto, T., & Namiki, M. (2010). Androgen replacement Therapy contributes to improving lower urinary tract symptoms in patients WITH Hypogonadism and BENIGN PROSTATE hypertrophy: A randomised controlled study. The Aging Male, 14(1), 53–58. https://doi.org/10.3109/13685538.2010.518178
    Cholesterol Changes
    1. Singh, A. B., Hsia, S., Alaupovic, P., Sinha-Hikim, I., Woodhouse, L., Buchanan, T. A., Shen, R., Bross, R., Berman, N., & Bhasin, S. (2002). The effects of Varying doses of T on insulin Sensitivity, Plasma LIPIDS, Apolipoproteins, AND C-reactive protein in healthy young men. The Journal of Clinical Endocrinology & Metabolism, 87(1), 136–143. https://doi.org/10.1210/jcem.87.1.8172 
    2. Whitsel, E. A., Boyko, E. J., Matsumoto, A. M., Anawalt, B. D., & Siscovick, D. S. (2001). Intramuscular testosterone esters and plasma lipids in hypogonadal men: A meta-analysis. The American Journal of Medicine, 111(4), 261–269. https://doi.org/10.1016/s0002-9343(01)00833-6
    Sleep Apnea
    1. Rhoden, E. L., & Morgentaler, A. (2004). Risks of testosterone-replacement therapy and recommendations for monitoring. New England Journal of Medicine, 350(5), 482–492. https://doi.org/10.1056/nejmra022251 
    2. Grech, A., Breck, J., & Heidelbaugh, J. (2014). Adverse effects of testosterone replacement therapy: An update on the evidence and controversy. Therapeutic Advances in Drug Safety, 5(5), 190–200. https://doi.org/10.1177/2042098614548680 
    3. Hoyos, C. M., Killick, R., Yee, B. J., Grunstein, R. R., & Liu, P. Y. (2012). Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: A randomized placebo-controlled trial. Clinical Endocrinology, 77(4), 599–607. https://doi.org/10.1111/j.1365-2265.2012.04413.x 
    4. Killick, R., Wang, D., Hoyos, C. M., Yee, B. J., Grunstein, R. R., & Liu, P. Y. (2013). The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: A randomised, placebo-controlled trial. Journal of Sleep Research, 22(3), 331–336. https://doi.org/10.1111/jsr.12027 
    5. Cole, A. P., Hanske, J., Jiang, W., Kwon, N. K., Lipsitz, S. R., Kathrins, M., Learn, P. A., Sun, M., Haider, A. H., Basaria, S., & Trinh, Q.-D. (2018). Impact of testosterone replacement therapy on thromboembolism, heart disease and obstructive sleep apnoea in men. BJU International, 121(5), 811–818. https://doi.org/10.1111/bju.14149
    Graphs
    • Figure 1
      • Adapted from Simon, D., Preziosi, P., Barrett-Connor, E., Roger, M., Saint-Paul, M., Nahoul, K., & Papoz, L. (1992). The influence of aging on plasma sex hormones in men: The telecom study. American Journal of Epidemiology, 135(7), 783–791. https://doi.org/10.1093/oxfordjournals.aje.a116365
    • Figure 2 –
      • Adapted from Oddens, B. J., & Vermeulen, A. (1996). Androgens and the Aging male: Proceedings of a Workshop organized by the international Health Foundation, Geneva, December 1995. Parthenon Pub. Group.
    • Figure 3
      • Adapted from Saad, F., Aversa, A., Isidori, A. M., Zafalon, L., Zitzmann, M., & Gooren, L. (2011). Onset of effects of testosterone treatment and time span until maximum effects are achieved. European Journal of Endocrinology, 165(5), 675–685. https://doi.org/10.1530/eje-11-0221

    • Figure 4
      • Adapted from Saad, F., Aversa, A., Isidori, A. M., Zafalon, L., Zitzmann, M., & Gooren, L. (2011). Onset of effects of testosterone treatment and time span until maximum effects are achieved. European Journal of Endocrinology, 165(5), 675–685. https://doi.org/10.1530/eje-11-0221