Possible Side Effects of Treatment
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. Some of the most commonly encountered side effects are:
- Testicular Atrophy and Infertility
- Benign Prostatic Hypertrophy (BPH)
- Hair Loss
- Cholesterol Changes
- Sleep Apnea
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.
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 al and Shighehara et al 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.