This post takes an in depth look into testosterone replacement therapy (TRT) for males.  We will discuss various topics including

• The bodies natural production of testosterone
• Factors that contribute to low testosterone
• The importance of maintaining adequate testosterone levels
• Symptoms of testosterone deficiency
• Laboratory evaluation of testosterone
• Contraindications to testosterone replacement therapy
• Side effects of TRT to consider
• Natural ways to increase testosterone levels
• Various options for testosterone replacement
• Testosterone optimization

Natural Production

All humans naturally produce some level of testosterone.  In males, testosterone production occurs via a detailed signaling pathway that begins in the brain and ends in the testes

• The hypothalamus in the brain produces Gonadotropin-releasing hormone (GnRH)
• GnRH then stimulates the pituitary gland to release follicle stimulating hormone (FSH) and Luteinizing hormone (LH)
• LH and FSH then travel to the testes.  In the tests, LH stimulates Leydig cells to produce testosterone and FSH stimulates Sertoli cells to produce sperm and another hormone called inhibin
• Inhibin will actually travel back to the pituitary and inhibit further release of FSH
• • • • •  

Males begin life with approximately 700 million Leydig cells and they begin to lose about 6 million cells per year starting in their 20s.  This correlates to a testosterone decline of 0.3% to 1.5% per year starting in a male’s 20s.

When a male is found to have low testosterone, they can be categorized as having either primary testosterone deficiency (TD) or secondary testosterone deficiency

• Primary TD: Lab analysis will show low T & high LH/FSH.  The LH & FSH are increased/working to stimulate the testes, but the testes are unable to produce testosterone.  This is testicular failure and there are a number of different causes which include aging, trauma, genetics, chemotherapy & radiation.
• Secondary TD: Lab analysis will show low T & low LH/FSH.  Despite having low testosterone levels, the pituitary is not releasing increased amounts of LH/FSH in order to try and stimulate more production.  85% of all testosterone deficiency falls into this category and causes include pituitary tumors, low thyroid hormone, malnutrition and stress
• • • • •  

There is another term known as Adult-Onset hypogonadism.  This group accounts for 89% of all secondary TD and has no identifiable cause.  Meaning, the vast majority of males with testosterone deficiency have no identifiable cause for it. 

Contributing Factors

Although male testosterone levels begin to decline during the third decade of life, it is well established that some males maintain normal testosterone levels well into their 70s and therefore low testosterone is not simply a byproduct of aging.

Although the vast majority of men with low testosterone have no identifiable cause, there is plenty of evidence that shows numerous modifiable conditions and lifestyle factors being related to low testosterone.

• Stress: both acute stress (such as running a marathon) and chronic stress can contribute to low testosterone
• Smoking
• Depression
• Poor Sleep: Studies have shown that sleep loss will lower testosterone levels in healthy young men.  In one study, male subjects had a 10-15% decrease in their testosterone after just one week of sleeping only 5 hours per night
• Type 2 Diabetes/insulin resistance
• Obesity: Increased adipose tissue (fat) causing increased conversion of testosterone to estrogen.  Additionally, adipose tissue produces a hormone called leptin which travels to the testes and inhibits testosterone production.  Obesity also causes increased inflammatory cytokines within the body which also inhibit testosterone production.
• Alcohol use

Besides increasing libido, why is testosterone so important

Most males seeking out testosterone replacement therapy usually have a single goal in mind… increased libido.  But having normal testosterone levels is critical for many other areas of your health.  Having low testosterone levels has been associated with the following

• Cardiovascular disease: men with low T are at increased risk of cardiovascular disease
• Cognitive impairment: testosterone is needed for optimal brain function.  Studies confirm that men who maintain optimal testosterone levels as they age have significantly fewer symptoms of senility along with improved cognitive function compared to men with low levels of testosterone
• Decreased muscle, stamina and balance: testosterone increases fat free mass, reduces visceral fat, improves exercise endurance and improves balance.  Additionally, testosterone supplementation helps reverse sarcopenia and osteoporosis by improving bone mineral density.
• Increased inflammation: low testosterone causes expression of inflammatory cytokines.  It appears that testosterone regulates multiple and overlapping cellular and molecular pathways involving a host of immune cells and biochemical factors that converge to contribute to attenuation of the inflammatory process.  This has been termed Inflamm-aging
• Increased risk of non-alcoholic fatty liver disease: NAFLD increases risk of cardiovascular disease.  Subsequently, improving testosterone levels and preventing fatty liver will decreased CVD risk
• • • •  

What are the symptoms of testosterone deficiency

There are a number of different symptoms a male can experience secondary to low testosterone.  Given that many of the symptoms could be contributed to various other causes, many men do not even realize that they are experiencing symptoms associated with low testosterone.  The following symptoms have the strongest support for being symptoms of testosterone deficiency

• Low libido
• Poor morning erections
• Abdominal obesity
• Decreased muscle mass and strength
• Decreased bone mineral density and osteoporosis
• Inflammation and autoimmune disease
• • •  

Additional symptoms that could occur secondary to testosterone deficiency include

• Erectile dysfunction
• Depressed mood
• Fatigue
• Decreased vitality
• Cognitive impairment
• Insulin resistance
• Metabolic syndrome
• Type 2 diabetes
• Hypertension and Dyslipidemia
• •  

Additionally, there are validated questionnaires to screen for low testosterone.  They include the following and can be found online.

• ADAM Questionnaire
• SHIM Questionnaire

Laboratory Evaluation of low testosterone

Given that many of the symptoms of low testosterone are vague, it is recommended that men get laboratory evaluation of their testosterone levels for complete evaluation. 

The normal range for serum total testosterone is 300-1100 ng/dL.  Numerous factors can alter your T level on the day you test so the following is recommended.

• Check early in the morning (between 7am and 10am).  Men below the age of 45 have diurnal variations and therefore if testosterone was checked in the late afternoon, serum testosterone levels may be 20-50% lower than if tested in the morning.
• Make sure it has been 8 hours since your last meal and 24 hours since your last significant stressor (exercise) or sexual activity.  You should also avoid testing if you are acutely ill.
• • •  

Additionally, total testosterone doesn’t tell the entire picture.  It is recommended that males have their free testosterone & sex hormone binding globulin (SHBG) tested as well.  

The vast majority of your testosterone is bound to carrier proteins.  About 45% of total testosterone is bound tightly to SHBG and about 50% is weakly bound to albumin.  Testosterone is unavailable for bio activity (inactive) when bound to these proteins. The only testosterone that has any biological effect is the testosterone that is unbound to protein (aka FREE T)

Free (active) testosterone makes up only 1-3% of total testosterone. Hence the importance of checking your SHBG levels.  A male with elevated SHBG could potentially have low free testosterone despite a normal total testosterone

Examples

• A male with a total T of 1000 but only 1% free T would have a free T of 10ng/dl
• A male with a total T of 500 but with 3% free T would have a free T of 15ng/dl 

In the above scenarios, the male with the lower total T actually has more active (free) T.

Influences on sex hormone binding globulin (SHBG) levels include

• Genetics
• Estradiol —> as estradiol increases, SHBG increases
• T4 (thyroid hormone) —> as T4 increases, SHBG increases
• Insulin —> as insulin increases, SHBG decreases

Contraindications to TRT

Potential side effects of TRT have led to conservative recommendations as to when TRT should be used.  The following laboratory values and conditions should be evaluated before initiating TRT.

• Hematocrit: This is the percentage by volume of red cells in your blood.  Having a hematocrit that is too high can increase the risk of cardiovascular events such as stroke.  Since Testosterone replacement therapy is known to raise hematocrit, it is contraindicated if hematocrit is greater than 48%.
• Liver Function Tests (LFTs): routine monitoring is recommended as some studies have shown increases with TRT.
• Prostate Specific Antigen (PSA):  PSA is used as a screening tool for diagnosing prostate cancer and TRT is known to increase PSA.  TRT is contraindicated in men with untreated prostate or breast cancer or if PSA level is greater than 4.
• TRT is contraindicated in men who have had a major cardiovascular event within the past 3-6 months
• TRT is contraindicated in men with uncontrolled heart failure due to potential increased cardiovascular risk and increased fluid retention that occurs with TRT.
• Fertility:  Exogenous testosterone causes a decline in fertility and therefore is not recommended for men who wish to have children.
• Thrombophilia: TRT is contraindicated in males with history of Factor V Leiden, Anti-Cardiolipin Ab, deep vein thrombosis (DVT) or pulmonary embolism (PE). 

Additional side effects of TRT to consider 

Although the following are not contraindications to initiating TRT, males should be aware of these potential side effects

• Acne
• Edema due to fluid and electrolyte retention
• Elevated blood pressure
• Male Pattern Baldness
• Gynecomastia
• Apnea
• Insomnia

Natural ways to increase your testosterone levels

For males not interested in starting TRT or for those who have contraindications, there are various other ways to naturally increase testosterone levels

#1.  Increase Production

• Obesity, metabolic syndrome and insulin resistance —> Weight loss and improved insulin sensitivity leads to improved testosterone production.  
• Exercise —> increasing exercising will increase testosterone levels.  HIIT training has been shown in multiple studies to contribute to keeping a man’s testosterone at optimal levels.  Heavy strength/resistance training also increases testosterone levels
• Nutrition —> maintaining optimal levels of Vitamin A, Vitamin D, Zinc & Selenium will optimize testosterone production.  Supplementing with Ashwaganda can also lead to increased testosterone production.
• Sleep —> Optimal sleep improves testosterone production
• Stress management —> reducing stress improves testosterone production

#2 Testosterone transport —> Lower SHBG to increase free (active) T

• As discussed previously, SHBG will determine the amount of free testosterone in circulation
• The higher the SHBG, the lower the active testosterone present
• SHBG levels are determined by body composition, glucose metabolism and one’s fat to lean ratio
• Additionally, smoking, low protein diets & high caffeine levels all contribute to elevated SHBG

#3 Detoxification

Various toxins can lead to lower testosterone levels.  These include alcohol, marijuana, phthalates & pesticides to name a few.

Additionally, during natural steroid metabolism, testosterone gets converted to estrogen and DHT by enzymes.  Elevated levels of these enzymes can result in more testosterone conversion and therefore lower testosterone levels.

Testosterone is converted to DHT by 5-alpha reductase. The following foods, herbs and supplements may lower 5 alpha reductase activity and therefore increase testosterone

Foods that inhibit 5 alpha reductase

• Green tea
• Flax seed
• Soy
• Omega 3 fats

Herbs that inhibit 5 alpha reductase

• Saw Palmetto
• Chaste tree berry
• Black cohosh
• Stinging nettle root

Nutrients/phytonutrients that inhibit 5 alpha reductase

• Quercetin
• Omega 3 fish oils
• Krill
• L-lysine
• Rice bran

Testosterone is converted to estrogen by aromatase.   The following foods, herbs and supplements may lower aromatase activity and therefore increase testosterone

Foods associated with lower aromatase activity

• Dietary fiber
• flax seeds
• soy
• Grape seed extract
• green tea

Herbs associated with lower aromatase activity

• Stinging nettle root
• Ginkgo

Nutrients and Phytonutrients associated with lower aromatase activity

• Quercetin
• Vitamin C
• Zinc
• Resveratrol
• Melatonin

Options for Testosterone Replacement Therapy

If you and your physician decide that testosterone replacement therapy is right for you, there are multiple options available.  The following are the most common routes of administration along with preferences of Marathon Direct Primary Care.  The preferences should not be construed as medical advice and you should consult with your physician to determine the route, frequency and dosing that is right for you.

Subcutaneous/Intramuscular Injection

• Subcutaneous injection is the preferred route of administration at Marathon Direct Primary Care.
• There are two available forms: testosterone cypionate and testosterone enanthate
• Our usual starting dose is 100mg weekly and we prefer administration of 50mg twice weekly.
• Testosterone enanthate comes in a pre-loaded pen for easier administration but testosterone cypionate is cheaper.

Oral

• Kyzatrex is an FDA approved oral testosterone replacement therapy for males.  A reasonable alternative for those not wanting to inject testosterone weekly
• Twice daily dosing

Pellets

• Testosterone pellets can be implanted beneath the skin and are typically replaced every 3 months
• Not a preferred route of administration by Marathon Direct Primary Care due to the difficulty and hassle of making dosing adjustments. 

Topical

• Patches and creams
• We do not recommend these routes due to variable absorption rates amongst males

Testosterone Optimization

The FDA recommends testosterone replacement therapy for males experiencing symptoms with a testosterone level BELOW 300.

But many men can still experience symptoms despite having a total testosterone level within the reference range (above 300).  The following has been shown

• Total T levels below 430 ng/dl are associated with increased prevalence of low libido. 
• Total T levels below 345 ng/dl are associated with increased visceral fat, increased risk of type 2 diabetes and increased risk for depression

Therefore, the term testosterone optimization has been coined.  Testosterone optimization does not strictly focus on a lab value.  Instead, testosterone optimization focuses on the patient’s symptoms and on the known health benefits of maintaining optimal levels of testosterone.

As we have learned, males can potentially optimize their testosterone levels just through lifestyle modification and may not require replacement.

At Marathon Direct Primary Care, we recommend that all adult males OPTIMIZE their testosterone levels.  We recommend adult males receive a full evaluation by their physician to discuss their testosterone and whether or not treatment is right for you

All materials contained in this blog post are for informational purposes only and should not be construed as medical advice.  Please consult with your physician concerning any and all medical questions and/or problems.

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