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The goal of testosterone (T) replacement therapy is to achieve physiologic testosterone levels (450-600 ng/dL or so) and provide relief of symptoms and signs of low testosterone. These signs may include the following: fatigue, low sex drive, erection issues, anemia, low bone mineral density, decreased lean body mass, and depression.
First-line treatment strategy for low T levels is lifestyle modification. Weight loss, healthy eating, and exercise can increase T levels and reduce the symptoms and signs of testosterone deficiency. The treatments discussed below are relevant to men who have tried to optimize their lifestyle yet still have symptomatic low T. Treatment is indicated only under the circumstance of documented low T levels (2 morning total T levels < 300 ng/dL) in an individual who has the appropriate symptoms and signs. Low T in the absence of symptoms is not treated, nor are symptoms that might be attributed to low T in the presence of normal T levels.
“There’s more than one way to skin a cat.” And so, there are many options to treat symptomatic low testosterone levels. There is no best way to treat low T and it is of benefit to patients to have choices. Many options are effective, and a good urologist will work with the patient to determine which option works best for the individual (shared decision-making). There are a variety of testosterone preparations currently available including pills, gels, patches, trans-nasal agents, buccal (applied to the gums), pellets, and short-duration and extended-duration injections. There are also testosterone alternatives including clomiphene citrate, aromatase inhibitors, and human chorionic gonadotropin (HCG). Each option has advantages and disadvantages. Regardless of option choice, men being treated for testosterone deficiency will need regular follow-up visits and careful monitoring of their testosterone levels as well as their blood count and PSA (prostate-specific antigen).
The decision as to which form of testosterone replacement therapy to use depends upon several factors. These can include the desire to maintain fertility, the desire to maintain testicular size and function, or a baseline hematocrit level or baseline PSA level. Often factors such as patient preference and convenience, the cost of the product, and a willingness to accept transference risk play a major part in the decision. Similarly, medical concerns such as a person’s anti-coagulation status, the risk for blood clotting, history of breast cancer or gynecomastia (man boobs); and history of cardiovascular events can affect the decision.
Desire to Maintain Fertility
Many patients are unaware that testosterone treatment negatively affects fertility and in fact functions as a male contraceptive. When the body is exposed to external testosterone, it is sensed by the pituitary gland and both native LH (luteinizing hormone) and FSH (follicle-stimulating hormone) are inhibited. This results in the testes essentially shutting down with a marked reduction in testicular testosterone production and sperm count. After terminating testosterone therapy, the time course and degree of sperm recovery are highly variable.
To maintain fertility, an alternative medication, i.e., clomiphene citrate can effectively increase testosterone levels by stimulating native testosterone production and preserve, if not, improve one’s sperm count since this medication is often used to help manage fertility issues in men.
Desire to Maintain Testicular Size and Function
To reiterate, when the body is exposed to external testosterone, it is sensed by the pituitary gland and both LH and FSH are inhibited. This results in the testes shutting down with a marked reduction in testosterone production and sperm count. Eventually, the testes will suffer disuse atrophy and can shrink substantially in size. Men on long-term testosterone replacement therapy will often end up infertile and with small testicles.
Again, not the case with a medication like clomiphene citrate that preserves testes size and function.
Baseline Hematocrit Level
Hematocrit is a measure of hemoglobin concentration in the blood. Testosterone stimulates red blood cell production and as a side effect can raise hematocrit to high levels (polycythemia). With the increased viscosity of blood, there is a risk of blood clots occurring (deep venous thrombosis and pulmonary emboli). If one has a high baseline hematocrit level (>50%), testosterone may not be a prudent option until the source of the elevation is evaluated and managed. Common causes of baseline elevated hematocrit include obstructive sleep apnea, pulmonary disease, and living at high altitudes.
Baseline PSA Level
Testosterone stimulates prostate growth and PSA (prostate specific antigen) release, just as an anti-androgen can shrink the prostate and lower PSA. If one has an elevated baseline PSA, it is imperative to further evaluate him to ensure that prostate cancer is not the underlying source of the PSA elevation. This is important because testosterone therapy in the face of untreated prostate cancer is not prudent.
Patient Preference and Convenience
This is one of the most important factors. There are many forms of testosterone delivery, and some are simply more appealing to any given patient than alternatives. Some can be self-administered, while others will require office visits to administer.
Cost
This is obviously a key factor.
Willingness to Accept Transference Risk
A problem with testosterone gels is that if any of the gel contacts the skin of a patient’s wife, child, another person, or pet, they will receive an unwanted dose of testosterone. This can potentially result in the wife growing a moustache (virilization), the child going through early puberty (precocious puberty), and the pet becoming more aggressive!
Whether the Patient Is Anti-Coagulated
Testosterone injections or pellet insertion are potentially more problematic in the patient who is anticoagulated, as bleeding, bruising, or hematoma formation may occur at the injection or insertion site.
Blood Clotting Risk
Since testosterone can raise hematocrit and result in venous blood clotting, if a patient already has had issues with blood clotting, testosterone therapy may not be a prudent choice.
History of Breast Cancer or Gynecomastia
Testosterone therapy will increase serum testosterone as well as estrogen levels. Testosterone should be used with great caution in a man with prior history of breast cancer because of the potential stimulatory effect on breast tissue. Gynecomastia (man boobs) is a risk factor for breast cancer and testosterone therapy should be deferred until a mammogram and perhaps ultrasound proves to be normal.
History of Cardiovascular Events
Low testosterone has been associated with obesity, type 2 diabetes, metabolic syndrome, and atherosclerosis. Studies have shown that men with lower testosterone levels are at greater risk for cardiovascular mortality as compared with men with higher testosterone levels. Thus testosterone may serve as a predictive marker for men at high risk for cardiovascular disease (atherosclerosis, heart attack, stroke, aneurysm, etc.). That stated, there is conflicting and confusing data on whether testosterone supplementation increases the risk for cardiovascular events or is protective against such occurrences. Current guidelines recommend postponing testosterone replacement for 3-6 months in men who have experienced a recent cardiovascular event.
In My Humble Opinion
When a man with testosterone deficiency requires treatment, the goal is to achieve physiological levels of testosterone and improve the symptoms and signs of the deficiency while minimizing the side effects and the cost. Clomiphene citrate is a once-daily pill that will often achieve these goals and is often my go-to first-line treatment. It is generic, relatively inexpensive, has minimal side effects, and does not adversely affect fertility or testicular size.
Bottom Line: Urologists and their patients have many therapeutic options for managing testosterone deficiency. Choice of management is predicated on the careful integration of numerous factors and shared decision-making. Clearly, one size does not fit all.
