Testosterone Replacement Therapy is the new midlife crisis. Instead of getting a Harley Davidson, new sports car, and new wardrobe, men are looking to reclaim their youth with a new batch of hormones. Rejuvenation clinics are popping up everywhere and advertising older men with brand new ripped bodies. Joe Rogan even talks about it openly and recommends it to his friends on his podcast. The result has been a fourfold increase in testosterone users among 18 and 45 and a threefold increase in ages 56 to 64 (12). This data also doesn’t take into account underground users outside of standard medical practice. So, not only is overall testosterone usage increasing, the age at which people start on replacement is decreasing. The purpose of this article is not to recommend testosterone replacement but to understand what to expect if you and your physician decide replacement is appropriate. I will also help you know what works and what doesn’t increase natural endogenous production.
Can I Increase My Testosterone Production Naturally?
The answer to this is yes but typically not in ways men want to hear. Testosterone is produced by the Leydig cells in the testes but is primarily controlled in the hypothalamus and the pituitary gland. The hypothalamus signals the release of Gonadotrophin-releasing hormone, which signals the pituitary gland to release luteinizing hormone into the blood, which travels to the gonads, which produces and releases testosterone. This sequence is commonly referred to as the hypothalamic-pituitary-gonadal axis (HPG axis).
A common question is what supplements should I take to increase my testosterone? Many over-the-counter supplements promise to stimulate the pituitary enough to increase testosterone values, such as Tribulus Terrestris, Maca, Coleus forskohlii, Eurycoma longifolia, etc. However, in general, over-the-counter testosterone boosters either show no significant effect on testosterone in controlled studies, or the improvements are so nominal that they have no significant impact on body composition or well-being.
Improving Testosterone with Lifestyle
Supposably, testosterone values have been decreasing in the population for decades, possibly due to pollutants in the environment such as plastic PBAs and Phthalates, which interfere with the androgen receptors (13). Aging is said to reduce testosterone by 1 to 2% per year after 25 (15). But these studies don’t take lifestyle factors into account. Modern men in western society are less physically active, more prone to obesity, and have poor nutritional choices compared to previous generations. And as men age and raise families, they become less physically active and have more stressful environments.
So, before you go charging into the doctor’s office, ask yourself a few questions am I obese, do I have a workout routine, am I getting adequate sleep, am I coping with stress, do I have a proper diet? This might answer the question, why do I have low testosterone in the first place? Not only has obesity shown to be associated with low testosterone (14), but when obesity is reduced, testosterone levels can increase (4). Stress is an overlooked killer of testosterone production. The natural stress hormone cortisol shows a negative association with testosterone production (1). When cortisol levels are excessive due to stress, catecholamines such as dopamine, adrenaline, and noradrenaline suppress Leydig function and testosterone production (6). The number one killer of natural testosterone production is alcohol. Alcohol suppresses every part of the HPTA-Axis, which regulates testosterone production. Older men suffering from alcoholism are the most likely group to be hypogonadal (5). Both sleep deprivations and sleep quality impact natural testosterone production. Non-standard shift work, which impedes both sleep quantity and quality, increases the chances of hypogonadism, infertility, and semen quality (2).
Chances are you probably aren’t reading this article if you weren’t considering testosterone therapy. But here is the kicker. If you engage in these lifestyle changes, you may naturally raise your testosterone enough and decide you do not need testosterone replacement. You might also find out that even if your testosterone levels don’t change, all the lifestyle changes made you feel so good that you decide you don’t need testosterone replacement. The way you feel and the way your body functions is so much more than hormone levels.
Taking the Plunge
Testosterone replacement or therapy offers many benefits but also comes with risks. One of the benefits is that it provides you with control of your hormone levels. Once you reach peak plasma concentrations, it becomes easy to predict serum testosterone levels based on your dosage. In general, most people get between 3 and 5 times the dosage in nanograms (ng) per deciliter (dl) of blood. So, in the middle of the bell curve, a 200mg weekly dose will get most people 800 ng/dl of testosterone at peak plasma concentration. Some outliers get a lot more and less based on genetic differences in hormone metabolism and aromatization rates. The main benefit is that even if you have a newborn at home, you’re living off 4 hours of sleep, and your job is to find landmines with a metal detector, your testosterone will still be where you want it to be. You won’t see the expected declines that you do with someone who relies on their natural production. The main objectives for testosterone users are increased protein retention (muscle mass) and sexual function. But testosterone offers many other benefits such as improved insulin sensitivity, improvements in phlebotomy (red blood cells & hemoglobin), improved cognition, and improved recovery from workouts.
One of the benefits or drawbacks of testosterone replacement is that you tend to get more estrogen conversion from the needle than from your natural production. Estrogen in men has been unfairly demonized based on a lack of understanding of the nature of Estrogen and its benefits. I like to say, “estrogen is like cocaine or whisky,” “more is better until it’s too much.” Estrogen is an essential hormone in males. The list of benefits includes calcium retention, connective tissue repair, increased insulin-like growth factor (IGF-1), the elevation of HDL cholesterol, and improved libido and sexual function. Not only is testosterone anabolic, but Estrogen is as well. Estrogen interacts with growth hormone to raises IGF-1, which facilitates tissue growth and repair. Issuing the estrogen receptor blocker, Tamoxifen has been shown to reduce growth hormone secretion in adolescent boys (9).
Many hormone replacement clinics automatically prescribe aromatase inhibitors (AI) to control Estrogen. I believe this to be an unwarranted practice. They are misguided, or it’s just easier to prescribe the same testosterone dose with an AI already to thousands of patients, so there doesn’t have to be an oversight. But a more appropriate practice would be to wait to see if any estrogenic side effects occur before adding any estrogen control. The amount of aromatization of testosterone into Estrogen is based on body fat levels, age, genetic factors, lifestyle factors such as alcohol and cigarette use, and even the intensity of physical activity. The actual estrogen plasma levels also do not fully determine unwanted effects. For example, medically normal estrogen levels in males are between 20 and 55 picograms/milliliter (pg/ml) (3). That is a relatively large range, and some subjects can get Estrogen related effects within this range, and some can go far outside of this range and get no estrogen-related side effects.
Elevation of Estrogen can cause gynecomastia (growth of breast tissue), water retention and elevated blood pressure, changes in mood, acne, and erectile dysfunction. When any of these unwanted effects occur, there are several options to mitigate them. The first option is to wait to see if the adverse effects are mitigated over time. This is highly dependent on the type of negative effect. It is best not to wait on the onset of gynecomastia, but acne and water retention may dissipate in a few weeks. The body is excellent at adaptation, and side effects may dissipate after a few days or weeks. Side effects may subside if you were previously obese and are in the process of losing weight. As fat cells get smaller, aromatase enzymes may be reduced, lowering Estrogen naturally. The next option is to lower the dose. This is probably the least popular option but probably the most appropriate based on long-term health and doesn’t have to be a permanent change. This could be very dependent on blood testosterone concentration. If you are taking 150mg per week and your testosterone is 1200 ng/dl, you are a high responder, and it may be appropriate to lower the dose to 100mg per week. If you are 800 ng/dl or lower, you may mitigate adverse effects by reducing the dose by as little as 20mg because 20mg out of a 200mg dose is a 10% reduction which is substantial. The goal is to use the scientific method to find out where your Estrogen can be without adverse effects. It is beneficial to start on a lower dose, such as 100mg per week, and keep bumping it up every three months until you find an ideal dosage based on how you feel and adverse effects.
If estrogenic side effects continue despite a lower dose or you have better function on a higher amount. The next course of action is to increase injection frequency if using injections. Using smaller, more frequent injections may reduce some of the conversion of testosterone to Estrogen. Testosterone Cypionate, for example, has a half-life of 8 days, so it isn’t necessary to inject more than once per week. But injecting twice or three times per week may prevent a prominent peak of testosterone which encourages estrogen conversion. The risk of more frequent injections is more holes in the body which means more pain, scar tissue, and more chances of infection.
Aromatase inhibitors (Ais) are another means of estrogen control. The use of Ais is a controversial subject because some doctors blanketly prescribe them to men on TRT, some doctors only use them to get Estrogen into what they believe is a sweet spot, and some doctors such as my own do not even order estrogen testing if there are adverse symptoms. Ais were developed to suppress estrogen-sensitive breast cancer in women. And now are prescribed off-label to control Estrogen in men as well. Most of the data available on the effects of AIs comes from women with breast cancer. In these populations, AIs are shown to be cardiotoxic (8), but it is unknown if the cardiovascular deterioration is solely due to the suppression of Estrogen or in combination with the aromatase inhibitor. This area needs more research, but at the very least, I believe AIs should be avoided unless estrogenic side effects cannot be mitigated through other means.
Dihydrotestosterone (DHT) and the Prostate
Starting in the 1950s, pharmaceutical companies began searching for ways to change testosterone molecules to make them more anabolic and less androgenic. This led to the discovery of many prescription anabolic-androgenic steroids. Researchers even created a ratio scale or androgenic-to-anabolic rating based on how anabolic the drug was compared to how androgenic it was. For example, they determined how androgenic the compound was based on how much it encouraged growth in the prostate. The molecule responsible for the androgenic properties of testosterone is the conversion into Dihydrotestosterone (DHT). DHT is responsible for the masculinization of men, women, and children. So, this includes the growth of the body and facial hair, enlargement of the penis or clitoris, prostate growth, enhanced sexual and reproductive performance (erections), and enhanced capacity for aggression. Thus, DHT is essential for proper function in both men and women. Still, it is the most harmful sex hormone at supraphysiological levels, leading to male pattern baldness, enlarged prostate, skewed lipid profiles, raised blood pressure, and over-aggression or anxiety. High natural testosterone levels are not associated with cardiovascular disease, but high DHT and free DHT levels are associated with cardiovascular disease (11).
It isn’t typical for doctors to order blood tests for DHT levels but instead for prostate antigen (PSA) levels. A slight elevation in PSA is not a reason to be concerned because if you were genuinely hypogonadal, then elevating your testosterone back to normal will return prostate antigens to a higher level as well. Although the research is still sparse, there is no data to support that replacement levels of testosterone supplementation directly cause benign prostate hyperplasia (enlarged prostate) (7). It is more likely that enlarged prostate is the result of age-related factors. If your prostate is a concern, you may want to talk to your doctor about starting 5mg of daily tadalafil (Cialis), which is prescribed for sexual function and prevents enlargement of the prostate.
Fertility and Testicular Atrophy
Fertility is a critical area to consider when it comes to hormone replacement. Suppressing the HPG axis through hormone replacement is likely to suppress fertility to some degree. So, suppose you are interested in having children in the future. In that case, it is essential to consider the risks and the possibility that you may have to stop using replacement hormones until pregnancy occurs. But many are misguided in the notion that hormone replacement automatically leads to sterility. Pharmaceutical companies have tried and failed for over 50 years to find an approved medication for male birth control. The world health organization (WHO) conducted two studies to determine if testosterone was a viable contraceptive for males. They used less than 3 million sperm as a basis for infertility, and only 64% reached the required level of sperm count, which is a majority and means that 46% of the subjects were still considered fertile. Therefore, testosterone could not be recommended as a viable contraceptive (10). So, infertility is not a guarantee. Many of the new clinical trials for male birth control contain a testosterone derivative combined with a progestin to suppress sperm production completely.
It would not be ideal to assume TRT will make you infertile. The best thing to do would be to get a fertility test before your start and then every six months to determine how much suppression the testosterone is giving you. If you are struggling with infertility, there are some options. In the WHO studies, subjects returned to average sperm production within five months. So you may choose to go off TRT until conception. Another option is to supplement with fertility medications as well. The most common one prescribed is human chorionic gonadotropin (HCG). HCG stimulates testosterone production in the testicles and sperm production as well. Doctors can prescribe a few other medications, such as HMG, Gogadorelin, and Clomid, which work through different pathways but produce similar outcomes. Additional benefits to HCG are preventing testicular atrophy and improving sexual function, libido, and seminal load. Especially useful if you are an adult film star. The main drawback of HCG is that it acutely stimulates a significant surge in testosterone production and results in substantial conversion to Estrogen. This may produce estrogenic side effects, most notably water retention. It is common to see a glazed-over look after your HCG injection because of the water retention. I am not a fan of using HCG unless it is required for fertility because of the potential estrogenic side effects. Some men who aren’t worried about conception also take HCH to keep their testicles their average size, which is a personal choice.
One of the benefits of testosterone is that it typically increases hemoglobin and red blood cell count. But this could potentially be a drawback and put you at higher risk for blood clots, stroke, and heart attack. Testosterone derivatives can be prescribed for anemia, and if you are on the low end of hematocrit (blood volume), testosterone may improve your physical endurance. But doctors get concerned when hematocrit is 50 and above. When above 50, that means that more than 50% of your blood is cellular proteins, and the other 50% or less is water. This concerns doctors because having high hematocrit signifies other life-threatening conditions such as heart disease or sleep apnea. But living at a high altitude also raises hematocrit, and there is no evidence that high altitude living causes heart attack and stroke. So, this is an area that needs more research.
But I will say that it is better to be safe than sorry. There are a few ways to manage hematocrit levels. The simplest way is to drink more water. As you increase the volume of water in the blood, it lowers hematocrit. Cardiovascular training lowers hematocrit mostly from reductions in hemoglobin. Cardiovascular exercise causes some damage and cell turnover in phlebotomy, reducing the volume of blood cell proteins. Many clinics and doctors advise donating blood, even every 60 days. This is not without some controversy. Donating blood will lower hematocrit temporarily. It is also a kind thing to do as hospitals are in constant need of blood reserves. But donating blood also triggers the upregulation of blood cell production, so it is only a temporary solution. It is also possible to end up with low ferritin (iron) in the blood with too frequent donations. If none of these methods work, you can try a supplement called IP6, which blocks some of the absorptions of iron. With less iron, you will have less potential for phlebotic production. The inherent risk of using IP6 is that again; you end up with low ferritin or anemia. If your hematocrit gets 50 or above, it may be helpful to start taking an 81mg aspirin to prevent clotting. The risk of aspirin use is excessive bleeding when cut and irritation and erosion of the stomach lining, so talk to your doctor about all these protocols.
Commonly Asked Questions about TRT
Q: When will TRT kick in?
A: Testosterone starts working as soon as it is freed from the ester and enters the blood, but you will not notice the effects until at least eight weeks, and the full effects won’t be noticed until peak plasma concentration at severe months. TRT is a life-long slow process, and depending on the ester and how long it takes to reach natural suppression will determine when you feel a big difference.
Q: Will Testosterone Help with Sexual Function?
A: It depends. Testosterone mainly helps with erections by improving nitric oxide production, which relaxes blood vessels and allows blood flow to the penis. But erectile dysfunction can have many causes. In addition, testosterone is not known to work better than PDE5 inhibitors such as sildenafil and tadalafil but may work synergistically.
Q: Will TRT increase my libido?
A: It depends. Libido is complex for behavioralists to quantify, but Estrogen is generally the primary driver of libido in men and testosterone in women. So, if TRT increases your Estrogen, it may also increase your libido.
Q: Why did TRT raise my cholesterol?
A: Testosterone has shown to improve cholesterol numbers in men when it gets them up and moving. But cholesterol is the substrate by which testosterone is manufactured by the body. If you stop the production than the substrate starts to build up. Without proper diet and exercise TRT can raise LDL cholesterol.
Q: Will TRT give me roid rage?
A: Testosterone is associated with aggression, but testosterone replacement hasn’t been shown to elevate aggressiveness outside of supraphysiological levels. The hormones primarily responsible for “roid rage” are 19-Nortestesterone derivatives such as nandrolone and trenbolone. Trenbolone is not an FDA-approved medication, and nandrolone is not commonly prescribed, but some clinics do.
Q: Will TRT make me bald?
A: Male pattern baldness is believed to be primarily a genetic condition. But elevated DHT may increase the progression of hair loss. There is no guarantee that TRT will elevate DHT above normal physiological levels. If hair loss occurs, you may talk to your doctor about topical DHT blockers or internal DHT blockers such as Finasteride. DHT blockers are known to have side effects such as erectile dysfunction.
Q: If I stop TRT, will my body ever produce testosterone again?
A: This depends on many factors, such as age and duration of use. Some people’s natural production will return to normal within and few months, and others may be up to 2 years. It is possible that testosterone production won’t return to previous levels if you have been on TRT for a substantial period, such as several years.
Q: Are Creams, Gels, and Pellets as good as an injection?
A: Injections are the easiest way to control the amount of testosterone you have and make changes. Pellets are inserted under the skin, and whatever testosterone level they bring you too you are stuck with until it is degraded, removed, and replaced. Gels have a low absorption rate and may be appropriate for women and geriatrics who need a lower testosterone level. Creams rubbed on thin skin, such as the scrotum, can be effective but have a higher variability based on how much you sweat and the thickness of your skin. Also, with transdermal cream, you risk transferring it to people who touch your skin near the application, such as a sexual partner.
Q: Where is the best place to inject?
A: It is intelligent to move injections around different sites in the body to prevent the buildup of scar tissue in the area. Many clinics recommend the quads because they are in the anterior of the body and are a large mass. The quadriceps are decent to inject but have a higher potential of hitting arteries and nerves with the needle. Injecting in the quads also causes more post-injection pain. The central part of the glutes is also a large mass with less potential for hitting blood supply and nerves. Shoulders are also good places to inject, but you have to be mindful of the size of your shoulder and the length of your needle.
Q: Will TRT make me look like a fitness model?
A: This is primarily based on your genetics, drug response, and many other factors. The short answer is that if you bring your testosterone higher than it was as a young man, you will see faster progress in your physique. But without good training, diet, superior genetics, do not expect miracles. Fitness models and athletes are typically on supraphysiological hormones, may use other performance-enhancing drugs, and often have excellent genetics.
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