Androgen Deficiency & Hormone Manipulation in Males

Background

What is testosterone and where does it come from?

Testosterone is a hormone produced predominantly in the testes (95%) with a small amount produced in the adrenal glands (5%)

Testosterone has many functions in the body.

Testosterone plays a role (though is rarely the only factor) in a great number of bodily functions.

It is responsible for:

• Skin: Hair growth, male pattern balding, production of sebum

• Liver: Synthesis of serum proteins

• Bone: Accelerated linear growth, closure of the growth plates

• Male sexual organs: Penile growth (only sensitive during puberty), sperm production, prostate growth and function.

• Brain: Sex drive, mood, (? Cognition)

• Muscle: Increase in strength and volume

• Kidney: Stimulation of red blood cell production (via erythropoietin)

• Bone marrow: Stimulation of stem cells.

Testosterone levels change with age.

• Prior to puberty: Levels are very low (with the exception that there is a spike in the fetal/neonatal period)

• At puberty: Testosterone levels rise rapidly to adult levels.

• In adults, there is a gradual decline in testosterone levels starting in the 30s with the rate of decline being more rapid in order males. There is significant debate as to how much decline should be considered a natural aging process versus a disease. By way of analogy, no one would consider menopause in females to be a disease process.

Testosterone levels vary through the day.

• The highest levels are observed in the early morning (between 3-8 AM) and lowest levels in the afternoon. A change in secretion over the course of the day is known as circadian variation'.

• This effect is most pronounced in younger males where there can be a 25% variation between morning and afternoon testosterones)

What is Hypogonadism?

The definition of hypogonadism varies depending on who you speak to.

• The Food and Drug Administration (FDA)defines hypogonadism as a testosterone lower than roughly 10 nmol/L.

• From a functional perspective, hypogonadism is the failure of the testes to produce sufficient testosterone and sperm.

However, these definitions are unsatisfactory from a clinical perspective. There is wide variation in measured testosterone levels and sperm production such that laboratory measurement alone is very limited in its ability to diagnose hypogonadism 

A better way to approach hypogonadism is to define it as a syndrome (a constellation of clinical and laboratory findings) and appreciate that there is no one specific test that can make the diagnosis or determine what treatment should be used. (AUA Guidelines; moderate recommendation; Evidence level Grade B).

1. Low testosterone level. There are many different ways to measure testosterone levels, but using a total testosterone level of about 10 nmol/L (this is equivalent to 300 mg/dL)

2. Symptoms and signs suggestive of hypogonadism:

   1. Physical/metabolic: muscle mass, energy and strength, difficulty building muscle

   2. Psychological: low mood, 'mental foginess', sleep disturbance.

   3. Sexual: decreased libido, orgasm, erectile function 

Note that these symptoms are non-specific and can be associated with a number of conditions, including 'life'. There is no agreed upon set of symptoms or lab test that establishes the diagnosis. The overall clinical picture needs to be considered.

Causes

The failure to produce a satisfactory level of testosterone may be the result of: 

• Secondary: An issue with the hypothalamus or pituitary

• Primary: An issue with the testis itself

There are a number of general as well as specific conditions that can cause both primary and secondary testicular failure.

• General conditions: Obesity, severe systemic illness, alcohol abuse, anabolic steroid use or abuse, inflammatory diseases, diabetes, chronic renal insufficiency, liver disease.

• Specific conditions: Absence or injury of the testes (chemotherapy, radiation, infection or trauma)'s, genetic conditions (such as Klinefelter syndrome).

There are multiple medications that have been associated with low testosterone. Examples include:

• Cardiac medications: Antiarrhythmics, high doses of lipid lowering agents, thiazide diuretics

• Hormone medications: Any kind of estrogen, progestins, steroids

• Chemotherapeutic agents

• Antifungal medications

• Opioids (for example, morphine, codeine)

Diagnosis & Evaluation

There are multiple symptoms that have been associated with hypogonadism. A major issue, however, is that NONE of the symptoms are specific for hypogonadism. In fact, many of the symptoms are simply the result of modern life (work, stress, poor diet, mood depression, etc.). Other symptoms, such as erectile dysfunction, or on the basis of cardiovascular disease. Consequently, symptoms alone cannot make the diagnosis.

When should testosterone levels be measured?

It is currently recommended that they should only be measured under 2 circumstances (AUA Guidelines moderate recommendation; evidence level grade B):

1. If symptoms suggestive of low testosterone are present

2. If the patient has a condition which would predispose them to low testosterone even in the absence of symptoms 

Note that measurement of testosterone levels for routine screening or in older males is NOT recommended.

Measurement of Testosterone 

Note: to convert conventional units (ng/dL) to SI units (nmol/L), multiply CU by 0.035

It is important to recognize that testosterone is distributed through the body in the bloodstream and that most testosterone is not 'free-floating'. In normal males, the breakdown of testosterone is:

1. Approximately two thirds (2/3) to albumin (a protein and from which the testosterone can easily dissociate and become active)

2. Approximately one third (1/3) bound to sex hormone binding globulin (SHBG).

3. A very small amount (about 2%) free testosterone.

Bioavailable testosterone (testosterone which exerts action on cells) = testosterone bound to albumin + free testosterone (= 2/3 of total testosterone).

• Total testosterone: This is usually the initial test and measures all 3 types of testosterone. If within range, no additional testing is usually indicated.

  • Age 40-60: mean testosterone in healthy males 430-460 ng/dL = 15 nmol/L.

  • Age 70-80: mean testosterone in healthy males 380-400 ng/dL = 13.6 nmol/L.

  • The distribution (spread) of values in healthy males is VERY LARGE. Many normal men will be both higher and lower than this number.

    • For example, Roche's SHBG product standardized to men without symptoms of hypogonadis reports the following (Wheeler et al Clin Endorinol 2008):

      • 17-40 years of age: median 14.1 nmol/L (95% range 4.51-28.7)

      • >40 years of age: median 13.2 nmol/L (95% range 4.69-20.5)

• Free testosterone: This can be measured if the total testosterone is below the lower limit of the reference level.

• Sex hormone binding globulin: This can be measured separately.

Because there are many ways that testosterone is found in the blood, there are multiple different measurements of testosterone that can be performed. These results will vary between labs, the time of data measurement was taken, as well as randomly fluctuate. The variation within any individual varies between roughly 50-150% between tests. Use of 2-3 measurements reduces that variability to about 30%.

Don’t read too much into any individual level. There are multiple reasons for variation in testosterone and consequently it is oftentimes appropriate to repeat a testosterone level and ensure it has been done within a few hours of waking.

American Urological Association Guidelines on Testosterone Measurement

• Use a total testosterone below 10 nmol/L as a reasonable cut off in support of the diagnosis of low testosterone. (Moderate recommendation; evidence level grade B).

• Do not use free testosterone as the primary means of diagnosing testosterone deficiency.

• Consider measuring free testosterone with equivocal testosterone levels between approximately 6 and 10 nmol/L

• The diagnosis of low testosterone should only be made after two (2) total testosterone measurements that are taken on separate occasions with both conducted in an early morning fashion. (Strong recommendation; evidence level grade A)

• The testosterone should not be measured during an acute illness. There is no effect of food intake.

Additional testing for low testosterone may be indicated:

• Leuteinizing hormone: There is a strong recommendation to measure this in patients with low testosterone but there is an ongoing issue as to what to do with the information. Can consider a selective estrogen receptor modulator in patients with low testosterone plus low/low normal luteinizing hormone levels.

• Follicle stimulating hormone: Should be considered in patients of reproductive age.

• Prolactin: Recommended in patients with low total testosterone plus low or low normal LH level. If elevated evaluation for hyperprolactinemia should be undertaken.

• Complete blood count: Strongly recommended prior to initiation of testosterone therapy.

Treatment

Measurement and Monitoring

Monitoring of treatment results is always necessary. There are 2 things which we are looking for:

1. An increase in serum testosterone level to the target (see below)

2. Improvement in the symptoms for which the testosterone was prescribed.

What is the ideal target for testosterone?

At present, is unknown what the optimal level of testosterone is. The current recommendation is to adjust testosterone therapy dosing to achieve a total testosterone level in the middle to tertile of the normal reference range. (AUA guideline conditional recommendation; evidence grade level C) 

Target for most men is between about 15-20 nmol/L.

This number was derived by looking at 31 randomized trials that showed some benefit to testosterone therapy and assessing the median and weighted posttreatment level. There is a very large spread in testosterone levels for both normal men and those in whom benefit from testosterone therapy was noted. Consequently, the reference range is very broad. There is no single level that will fit all men.

It is important to measure testosterone in a uniform way to assess treatment response.

It is important that the blood is drawn at the same appropriate time as this can significantly affect the measured level. Timing differs based on the type of testosterone supplementation.

1. Testosterone injection: how we draw testosterone levels will depend on what we are looking for
   

   1. A 'peak' level can be drawn the day after the injection and a 'trough' level the morning that you are due for the injection. These will help determine the total dose and the frequency of dosing (the peak level corresponds with the risk of polycythemia and the trough with the potential symptoms of 'testosterone crash')

   2. Blood level should be drawn 1 (ONE) week after the last injection. The target level is between 400 - 700 ng/dl (or roughly 10-20 nmol/L)

2. Testosterone gels and patches: blood level can be drawn in the morning

3. Goto the same lab each time.

Calculating Bioavailable Testosterone by Measuring Total T, Albumin and SHBG

Treatment of Testosterone Deficiency

Testosterone replacement/supplementation can be very beneficial in select circumstances. However, testosterone replacement is not a “cure all” for men, despite much marketing to the contrary. There There are pros and cons to testosterone supplementation and these can be discussed with your physician.

Note that testosterone will increase libido and energy, but will not on their own improve erections.

Lifestyle Modification

All men with testosterone deficiency should be counseled regarding lifestyle modifications as a treatment strategy. These include weight loss, exercise, optimization of diet (high vegetable/fruit, low-fat), smoking cessation, moderation in alcohol. (AUA guideline conditional recommendation; evidence level grade B).

There are 2 general ways to increase testosterone levels

1. Give testosterone directly

   1. Skin gels

   2. Injections (into muscle or under the skin)

   3. Pills by mouth

2. Prompt the body to make more testostone

   1. Selective estrogen receptor modulators (SERM's)

   2. Aromatase inhibitors

   3. Gonadotropin releasing hormone (GnRH)

*May not be available in Canada yet

Formulations to increase the body’s own production of testosterone

These treatments are primarily used to treat men with infertility and in general are not used in men with hypogonadism. They can indirectly increase the levels of testosterone. Note that all of these medications are used 'off-label' and require subspecialty expertise for prescribing and monitoring.

Risks in the Treatment of Testosterone Deficiency

Testosterone Supplementation and Prostate Cancer

Advanced prostate cancer is often treated with medications that either lower or block the action of testosterone. Some people have assumed that increasing testosterone either causes prostate cancer in otherwise normal men or promotes progression of prostate cancer in men without advanced disease – this is probably not true. There is an absence of evidence linking testosterone therapy to development of prostate cancer. (AUA guideline strong recommendation; evidence level grade B). For the prostate cancer patient with testosterone deficiency, there is inadequate evidence to quantify the risk benefit ratio of testosterone therapy. (AUA guideline; expert opinion).

1. Men receiving testosterone supplementation to physiologic levels should not worry about an increased risk of developing prostate cancer The incidence and types of prostate cancer are the same in men regardless of testosterone supplementation.

2. Men who have prostate cancer which is being observed (active surveillance) and which is not advanced, there is probably no risk or making the cancer worse if testosterone is supplemented to physiologic levels*

3. Men whom have had prostate cancer treated and in whom the disease is not advanced probably do not have any risk of progression if testosterone is supplemented to physiologic levels*

4. Men with advanced prostate cancer should avoid testosterone supplementation* 

*Talk to your urologist about the options and current evidence. Monitoring is always required. Advanced disease includes men who have disease which has spread outside the prostate to the lymph nodes or bone. It has been hypothesized that testosterone helps prostate tissue 'differentiate' into more normal tissue. There are clinical trials underway to answer these questions better.

Testosterone Supplementation and Cardiovascular Side-Effects

Low testosterone has been associated with an increased risk of cardiovascular disease. These include increased BMI, obesity, dyslipidemia, hypertension. (AUA guideline: Strong recommendation; evidence level grade B).  

Venous thromboembolic events No definitive evidence exists however only large observational studies of relatively short duration are available. As a consequence this issue is not settled. It may be that testosterone therapy unmasks a predilection to clot formation. (AUA guideline: Moderate recommendation; evidence level grade C)

Major Adverse Cardiovascular Events. Short term randomized controlled data does not show a significant difference in the incidence of MACE in men on testosterone therapy when compared to placebo. 8 randomized control trials show no difference in the incidence of myocardial infarction in testosterone therapy versus placebo. 6 randomized control trials show no statistically significant incidence of cardiovascular mortality in testosterone users. 3 randomized control trials show equal likelihood of the incidence of stroke between placebo and testosterone arms.

Men with low testosterone of an increased risk of cardiac event-related death as well as all cause mortality. However, it cannot be stated definitively whether testosterone therapy increases or decreases the risk of Major Adverse Cardiovascular Events (MACE) (AUA guideline: Evidence level grade B). Expert opinion is that testosterone therapy should not be commenced for 3-6 months in patients with a history of MACE.

References:

American Urological Association 2018 Guidelines on Testosterone Deficiency

AUA 2019 Update on Testosterone Deficiency

On the Web

General Urology Websites

Canadian Urological Association  Extensive library of downloadable pamphlets on a wide range of urological conditions

Cleveland Clinic

Mayo Clinic

Medline Plus Produced by the US National Institutes of Health with information on virtually every health topic and extensive list of links

UrologyHealth.org The patient information site of the American Urological Association.