Testosterone Replacement Therapy in Men: Exploring State-of-the-Art Practices

The patient population that the Naturopathic doctor is most likely to encounter is that of the man with late onset hypogonadism (LOH). Male menopause, low T and testicular hypofunction all refer to the fact that male total testosterone (TT) or free testosterone (FT) levels are low. Often the treatment is the same regardless of cause. Causes include testicular injury, obesity, hypopituitarism, head injury, opioid use, age, primary testicular failure, and congenital causes such as Klinfelter’s syndrome. Obesity decreases TT due to an insulin resistance-associated feedback loop mediated by reductions in sex hormone binding globulin (SHBG) and FT will go up marginally. Obesity can also suppress the hypothalamic-pituitary-gonadal axis (HPGA) leading to lowered TT and FT[1].

Poor diet and lifestyle choices including high stress and lack of sleep also contribute to low testosterone. TBI can disturb the communication between the hypothalamus and the pituitary. Male T levels normally fluctuate with a natural diurnal rhythm and are highest in the early morning and lowest right before bed. It is agreed that the diagnosis of low T can be made when TT is below 300 ng/dL on two separate morning blood draws.

The production of T is driven by the HPGA. Gonadotropin releasing hormone is secreted by the hypothalamus and drives production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through typical feedback loops like other hormones in the body. LH regulates the secretion of T by the Leydig cells, whereas FSH supports spermatogenesis[2].

Helpful data has been published over the years on the effectiveness of testosterone replacement therapy in the treatment of erectile dysfunction, low libido, depression, improving quality of life scores, osteoporosis, cognitive impairment, and metabolic syndrome. Testosterone replacement therapy does not need to be complicated; once a provider learns the nuts and bolts it is very easy to do.

Testing and Identifying Low Testosterone

The range for TT is 250-1100 ng/dL and for FT its 35.0-155.0 pg/mL. Some labs use a different range for free T using the direct methodology which is pg/mL 6.8-21.5. If T deficiency is suspected lab work should include TT, FT, estradiol, PSA, TSH, vitamin D, DHT, FSH and LH. If FSH and LH are elevated, and T is below 200 ng/dL, primary testicular failure is to be suspected.  If T is low and FSH and LH are normal or on the lower end, pituitary involvement is to be suspected. If the patient is overweight add lipids and A1c to the lab test. Patients should have these labs completed as a baseline before starting treatment.

Sex hormone binding globulin (SHBG) is not a very helpful test because if FT is low and TT is normal you know SHBG is high. FT is calculated by considering the binding effects of SHBG and albumin. SHBG is the main factor involved in regulating free T levels. Unfortunately, SHBG is hard to treat and sometimes individuals will run high levels for no known reason. SHBG can elevate with age, alcohol abuse, and a protein deficient diet especially in older men[3].

TT may be normal but FT low or, conversely, TT may be low and FT normal (usually just barely).  A symptomatic patient should be treated regardless. A good Naturopathic doctor will remember they are treating the patient, not the labs. If TT and FT are on the lower side but the patient has no symptoms treatment can be deferred.

If an overweight or obese man presents with concerns about T it clearly makes sense to check his endocrine system along with the other comprehensive work a Naturopathic doctor would do. It is not unusual to find low T. Often treating it can help the patient with energy, confidence, drive, and focus. This helps them stay on task with their diet, exercise, and lifestyle choices which all have a much larger impact on body composition.

How Testosterone Replacement Therapy has Evolved Over Time

Much has changed in the 22 years since I graduated from Naturopathic medical school. Back in the day, regular insurance-based doctors were reluctant to prescribe T. They would usually refer patients to an endocrinologist. This still occurs today but to a lesser extent with the advent of more acceptance and good safety/benefit data. Treating LOH can be done in a primary care setting and should not require a referral to an endocrinologist under typical circumstances. Circumstances in which a referral should be considered include concerns about pituitary health. Finding low T with poor or no response from the pituitary and/or abnormalities in TSH and prolactin is best to refer out. One cause of low T which may be overlooked is if the patient has a history of head injury. The most common cause is functional, involving the hypothalamus and pituitary communication with the testicles not primary testicular failure.

Injectable Testosterone

In the United States injectable T is bioidentical but bound to an ester to modulate half-life. There are three main types of T ester compounds: cypionate, propionate, and enanthanate. T cypionate is by far the most common. T cypionate has the longest half-life at seven days which makes it preferable in most cases. Shorter acting T compounds come with a higher risk of side effects like edema and acne.

In the past, T 200 mg/mL in a 10 mL vial was easily available. This made it convenient because at a typical dose of 100 mg per week the vial will last 20 weeks. Now most pharmacies will only dispense 1 mL vials at a concentration of 200 mg/mL providing only 2 weeks worth of T for the typical patient. They do this because of concerns of bacterial contamination of the vial. The downside here is the patient must go to the pharmacy more frequently and there is more waste because there is always some T left in the small vial. Compounding pharmacies can make a product with lower viscosity, supply more T per vial, and mail it directly to the patient.

Injectable T is convenient and effective because you can dose in 1/10^th of a mL increments with a 1 mL syringe. Most injectable T is 200 mg/mL and the typical dose for a man between 150 and 200 pounds is 100 mg per week (0.5 mL) once per week. Weekly doses given to patients in my practice vary from 0.3 mL on the low-end, upwards to .8 mL at the highest. Men who weigh more may need a higher dose.

Patients can be educated on injection technique and sharps protocol. At our practice we allow patients to dispose of their needles and sharps container and bring it in for proper disposal.  Gluteal injections are the least painful followed by deltoid and finally quadriceps. Some practitioners will advise patients to do subcutaneous injections. Subcutaneous injections are a different dosing strategy requiring more frequent very low dose injections but providing steady-state levels.

There is a new short acting T enanthate product that comes in an injector pen making dosing easy but it is much more expensive than generic T cypionate. A recent search on drugs.com listed a price of $583 for a 4-week supply at a dose of 100 mg per week. Prices range from as little as $60, up to about $120 for 10 ml / 200mg/ml generic T cypionate.

Transdermal Testosterone

T pellets, creams, patches, and sublingual troches are all bioidentical T without an ester. All compounded non-injectable hormones are purely bioidentical. Commercially available non-compounded transdermal preparations are also commonly prescribed by conventional physicians. These typically contain less T per gram than compounded.

These must be used daily and rubbed into the skin typically on the inside of both forearms.  There can be variability in absorption between different patients creating need for more follow-up and more changes to the dose. Patients with excessive adipose tissue may need a higher dose. Additionally, children and women can get exposed to T unwillingly through physical contact. I have found that there can be more difficulty maintaining consistent levels with topical preparations.

It’s more difficult to control the dose on commercial gels because the product comes with the pump and is either one or two pumps. With compounded preparations the perfect dose can be made for the patient. A typical patient will need 100 mg per day of compounded product.

The most common prescription T comes in a 1% or 1.62% gel. To get 50 mg 5 g of gel is needed to deliver just 50 mg of T, and 5 g of gel is a lot of gel. Prescribing T at too low of a dose can shut off endogenous production and even lead to lower T levels then baseline. This happens thanks to feedback inhibition, similar to how birth control pills work.

Sublingual Testosterone

Both oral tablets and sublingual troches are also available from compounding pharmacists. The dose is typically the same as transdermal and may be customized to the patient. Like transdermal compounded there may be great variability between patients regarding dose. Compounding pharmacists can be an invaluable resource.

Human Chorionic Gonadotropin (hCG)

The naturally occurring molecule hCG has recently been approved by the FDA for the treatment of hypogonadism[4]. It works by stimulating Leydig cells through a mimetic effect. HCG is similar enough to luteinizing hormone that it binds the receptor thereby increasing T production[5]. HCG was originally approved for treating undescended testes during puberty.

It can be used as a treatment for testicular atrophy in men on exogenous T. Some practitioners will cycle hCG with T to prevent this. A typical cycle would be three months on T with one month on hCG.  HCG can be used as a solo treatment or in conjunction with T. My preferred treatment for men on long-term testosteone replacement therapy is to use T with hCG all the time with no pulsing. I like using hCG with T because sperm count and testicular size can be preserved. Less exogenous T is needed.

A very typical dosing schedule would be 0.4 mL T cypionate with 1,000 international units of hCG per week. A 2016 study[6] in Aging Male suggested hCG is a preferred treatment for late-onset hypogonadism. Treatment of late onset hypogonadism with hCG improved vitamin D and T. Leydig cells play a role in 25-hydroxylation of vitamin D as well as production of T. HCG was shown to increase T with less side effects such as hyperestrogenism and polycythemia.

Clomiphene (Clomid)

Clomiphene citrate (CC) is frequently used off-label for the treatment of hypogonadism in men who want to maintain adequate sperm count. CC is a selective estrogen receptor modulator that antagonizes the estrogen receptors in the hypothalamus and pituitary gland[7]. This disrupts the natural negative feedback of estrogen and stimulates the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH). LH acts on the Leydig cells in the testis to increase T. Tamoxifen may also be used but our experience has not been as positive as clomiphene.

Pellets

Another good method is the T pellet. Small pellets are inserted underneath the skin in the buttocks area, and they typically last four months before T level starts to taper off. A small incision is made during a sterile procedure with an out of pocket cost of $300-400. The benefit here is that consistent T levels are obtained over a long-term period.

Follow Up After Testosterone Replacement Therapy

Ideally, lab work should be done every three months initially and six months thereafter. The blood draw should occur the morning the patient is due for their injection. Good target blood levels at the end of the week are approximately 450 ng/dL to 650 ng/dL. Free T levels may vary quite a bit and must be taken into consideration when looking at the total levels. Conventional physicians may be reluctant to train patients to do their own injections. Lab work should include a CBC, CMP, PSA, free and total T, dihydrotestosterone and estradiol.

Testosterone and Cardiovascular Disease

There is a strong association between low T levels and cardiovascular mortality[8]. Controversy still exists regarding the benefit/risk ratio of T replacement on Major Adverse Cardiovascular Events (MACE) but increasingly data supports a preventive effect. Previous studies did not control for patients with pre-existing cardiovascular disease adequately[9]. This older data proposed that men had increased MACE risk.

T therapy has been shown to improve symptoms of angina, increasing the time for ST depression to occur on treadmill testing[10]. Receptors for T exist within the artery wall that elicit vasodilatory response. T deficiency is associated with poor cardiovascular outcomes. In a seven-year study on men with vascular disease, T deficiency was associated with premature death (HR1.86 for all-cause mortality and of 2.50 for vascular mortality[11].

Shortcomings in Conventional Testosterone Replacement

Patients may be required to get their shots at the doctor’s office every two weeks. Additionally, I have found that PSA, estrogen, and red blood cell counts are not followed up on as frequently as they should be. I do not fault these doctors as they have their hands full and do not have special training in T replacement therapy. On the other side of the spectrum are ‘Low T’ clinics. What I found with these places is that a medical doctor typically rubber stamps everything. Some low T clinics charge excessive amounts in the form of membership dues upwards of $2,000-3000, requiring patients to pay out of pocket for the labs. I see men who have presented with completely normal T and have still been prescribed shots, sometimes at a dose so high that they get dangerous side effects. In some cases, the lab follow up is good, and in other cases it falls short. I routinely see patients go for years with hematocrits as high as 55 and red cell depletion was never discussed. Secondary polycythemia due to the increased erythropoiesis is a common side effect especially where I practice here in Colorado.

The Pros and Cons of Testosterone Replacement Therapy

From my over 20 years of clinical experience the following are my pros and cons of T replacement. An important point is that all the side effects can be mitigated.

Pros:

1. Improvement in erectile function and libido
2. Increased fat free body mass with prudent diet and exercise
3. Improved sleep
4. Improved cholesterol and triglyceride numbers
5. Increased energy
6. Improved athletic performance especially at altitude due to increased red blood cell count, improved vasodilation and oxygen carrying capacity from increased hematocrit
7. Improved exercise performance in endurance athletes who were training upwards of 12 or more hours a week and experienced low T as a result of endurance training
8. Improved vasodilation and resulting circulation
9. Big improvements in mood, confidence, and drive. In some cases, this is the biggest result. Many men make important life-changing decisions after being treated for low T.

Cons:

1. Secondary polycythemia requiring red cell depletion (500 mL 2-4 times per year). Polycythemia is an important concern because it increases viscosity. Increased blood viscosity can cause hypertension, increases the workload of the heart, and cause arterial damage. Arterial damage occurs due to sheer stress on the artery wall.
2. Elevated estrogen, which requires 0.5 mg of anastrozole once per week (DIM also helps). Hyperestrogenism can cause breast enlargement, mood swings, edema and prostate enlargement. Side effects are more likely to occur with larger fluctuations in blood levels compared to a more steady-state level.
3. Rare occurrence of acne. Acne usually only happens when the patient is overtreated.
4. Irritability and impatience
5. Elevated blood pressure if red blood cell count is not monitored and patient does not donate blood. This occurs because of increased blood viscosity.
6. Some men are sensitive to DHT and may get hair loss and prostate enlargement with elevated levels. It can also be treated with 5-alpha reductase inhibitors including saw palmetto.
7. Testicular atrophy/shrinkage, and infertility. This is reversible and does not cause sterility. It only occurs with exogeneous T administration at excessive dose. Complete atrophy is rare. Most older men beyond child rearing age do not mind if there is a minor decrease in testicle size, or fertility. Upon stopping T, testicles will return to their baseline size and sperm count will normalize to original levels.

 

If you suspect you may have low testosterone and would like to be tested and explore treatment, contact Dr. Steve Parcell at 303-884-7557.

 

 

References:

[1] Fui MN, Dupuis P, Grossmann M. Lowered T in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014;16(2):223-231.

[2] Ide V, Vanderschueren D, Antonio L. Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy. Int J Mol Sci. 2020;22(1):21. Published 2020 Dec 22.

[3] C. Longcope, H. A. Feldman, J. B. McKinlay, A. B. Araujo, Diet and Sex Hormone-Binding Globulin, The Journal of Clinical Endocrinology & Metabolism, Volume 85, Issue 1, 1 January 2000, Pages 293–296.

[4] Krzastek SC, Smith RP. Non-Testosterone management of male hypogonadism: an examination of the existing literature. Transl Androl Urol. 2020;9(Suppl 2):S160-S170.

[5] Ide V, Vanderschueren D, Antonio L. Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy. Int J Mol Sci. 2020;22(1):21.

[6] La Vignera S, Condorelli RA, Cimino L, Russo GI, Morgia G, Calogero AE. Late-onset hypogonadism: the advantages of treatment with human chorionic gonadotropin rather than Testosterone. Aging Male. 2016;19(1):34-9.

[7] Dadhich P, Ramasamy R, Scovell J, Wilken N, Lipshultz L. Testosterone versus clomiphene citrate in managing symptoms of hypogonadism in men. Indian J Urol. 2017;33(3):236-240.

[8] Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum Testosterone and increased mortality in men with coronary heart disease. Heart. 2010 Nov;96(22):1821-5.

[9] Gencer B, Bonomi M, Adorni MP, Sirtori CR, Mach F, Ruscica M. Cardiovascular risk and Testosterone – from subclinical atherosclerosis to lipoprotein function to heart failure. Rev Endocr Metab Disord. 2021;22(2):257-274.

[10] Oskui PM, French WJ, Herring MJ, et al. Testsoterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc. 2013 Nov 15;2(6).

[11] Gencer B, Bonomi M, Adorni MP, Sirtori CR, Mach F, Ruscica M. Cardiovascular risk and Testosterone – from subclinical atherosclerosis to lipoprotein function to heart failure. Rev Endocr Metab Disord. 2021;22(2):257-274.