Low Testosterone
As we've discussed throughout this article, the term 'endogenous' refers to something that is produced and secreted within the body, while the term 'exogenous' refers to something that is brought into the body from the outside, such as through ingestion or injection.
When the phrases "endogenous testosterone" or "natural endogenous testosterone production" or variations thereof are used, they refer to the body's own production and secretion of testosterone, which occurs in the Leydig cells of the testes.
Of course, exogenous testosterone is administered via various routes of administration, including transdermal administration, injection, or ingestion via oral tablets or capsules.
This section on testosterone covers endogenous testosterone production and the dynamics surrounding it, as well as the most important and most concerned and investigated aspect of today's society: low testosterone.
This subsection explores the dangers of low testosterone, the causes of low testosterone, common treatments for low testosterone, and considerations for those who wish to participate in long-term testosterone replacement therapy (TRT), one of the treatments for low testosterone.
A brief explanation of endogenous testosterone
How endogenous or exogenous testosterone works at the cellular and systemic levels in the human body was discussed in detail at the beginning of this article.
The manufacture and secretion of endogenous testosterone by Leydig cells in the testes is just one of several axis points in a larger network of axes known as the hypothalamic-pituitary-testicular axis (HPTA).
This is a component of the endocrine system, which is composed of a variety of hormones that act as signal transmitters through each axis, ultimately leading to the production of testosterone.
This endogenous testosterone production is the end product that most individuals are interested in, and the other hormones involved in the operation of HPTA act as intermediary (but very necessary) hormones in the functioning of endogenous testosterone production. An understanding of endogenous testosterone production and how HPTAs work to enable testosterone production is essential to an overall understanding of how the body secretes endogenous testosterone, the causes of low testosterone, how it can be treated, post cycle therapy (PCT) issues following an anabolic steroid cycle, and other specific details related to this aspect of the endocrine system.
The diagram shown above is an illustration of HPTA.
As previously described, the HPTA is a system of interconnected axes that regulate and determine endogenous testosterone secretion, which in turn determines the amount of testosterone circulating throughout the body at any given time.
The maximum amount of endogenous testosterone produced and circulating within each human body is predetermined by a set of "blueprints" and "instructions" in the form of genetics (DNA).
In reality, there are other determinants that affect the amount of testosterone an individual endogenously produces. These other factors include age, diet, body composition, lifestyle, and physical activity. All of these factors, in addition to the absolute determinant of genetics (DNA), act as the ultimate arbiters of how much endogenous testosterone is produced.
HPTA works through a system dynamic known as negative feedback.
This is specifically known as a negative feedback loop, which is a self-regulating mechanism of the system.
This negative feedback loop affects the behavior of the HPTA in a way that reduces variation.
In other words, when excessive levels of testosterone are detected circulating through the bloodstream, the body reduces endogenous testosterone production.
The HPTA then adjusts its output signal accordingly when it detects an excessive (or insufficient) amount of testosterone. This process of recognition and change is the basic description of how a negative feedback loop works.
This whole process is controlled by the hypothalamus, which literally acts as the "master" endocrine gland for all endocrine and hormonal processes in the body.
What causes the hypothalamus to determine whether there is 'too much' or 'too little' circulating testosterone is determined by the genetic code (DNA), as mentioned earlier.
This negative feedback loop is one of many processes involved in maintaining hormonal homeostasis in the body, but it's an important one.
Homeostasis is defined as the regulation of a system, which can be a computer system, a mechanical system, or an ecosystem. In this particular case, it refers to the body's internal systems, specifically the endocrine system.
This is done for the purpose of keeping the body in a stable, continuous, and satisfactory state.
All endocrine axes, and all endocrine glands within each axis, operate to a degree that fluctuates in some way through negative feedback loops.
HPTA is composed of and works with five hormones to maintain homeostasis, including
- GnRH (gonadotropin-releasing hormone)
- LH (luteinizing hormone)
- FSH (follicle-stimulating hormone)
- Testosterone
The first axis of the HPTA is the hypothalamus.
The hypothalamus monitors blood flow (as the contents of the plasma pass through the veins and capillaries) to detect the body's need to produce more endogenous testosterone and releases varying amounts of GnRH in response.
GnRH is a signaling hormone that tells the next axis point, the pituitary gland, to begin production and secretion of two other important signaling hormones known as gonadotropins: LH (luteinizing hormone) and FSH (follicle-stimulating hormone).
LH and FSH are the two hormones that carry the signaling process to the third axis point, the testes, to begin the synthesis and secretion of testosterone.
This is the final step and ultimately the goal of the final manufacturing and production of endogenous testosterone in HPTA.
The inhibition, reduction, suppression, and/or complete blockade of HPTA (and subsequent production of endogenous testosterone) is essentially determined by two main hormones:
- Excess testosterone
- Excess estrogen
Of course, there are other conditions and hormones that can interfere with and inhibit HPTA function, such as physical trauma to the testes or other hormones and hormonal factors such as progestins and prolactin.
However, if you're interested in normal feedback loops and how the body's own regulatory system inhibits (or stimulates) endogenous testosterone production, the two main hormones that play a decisive role here are testosterone and estrogen.
When the hypothalamus identifies excessive amounts of testosterone and/or estrogen in the bloodstream, it works to restore homeostasis through the opposite process described earlier.
That is, it suppresses or stops the production and release of various signaling hormones throughout the axis.
The excess of testosterone or estrogen that can signal this negative feedback loop can be caused by the use of exogenous androgens in an anabolic steroid cycle or even by endogenous imbalances in the body. There are a variety of factors that can influence this process.
When the hypothalamus reduces or stops the production of signaling hormones within the axis, essentially the opposite process occurs.
The hypothalamus stops releasing GnRH, which in turn stops the production of LH and FSH, which ultimately reduces or stops the production of testosterone in the Leydig cells of the testes.
Only after ideal hormonal homeostasis in the hypothalamus (determined by genetics and the other factors described) is restored does the secretion and release of the various signaling hormones within the HPTA resume.
This process can take several months before the body is able to function at normal levels again, and this is without the intervention of exogenous testosterone-stimulating compounds.
The time it takes for the body to accomplish this process under its own power depends on many factors, including the length of time it has been suppressed, the individual's genetics, and environmental factors.
Signs, symptoms, and dangers of low testosterone
At the time of this writing, awareness of low testosterone and its risks and disorders has increased dramatically over the past year or two.
More and more healthcare professionals and doctors are treating male patients with signs and symptoms of low testosterone, a diagnosis that is becoming more and more common with each passing year.
This is likely due to more men becoming aware of the condition rather than an increase in the incidence or prevalence of low testosterone.
It is a normal aspect of aging for men's testosterone levels to decline with age.
There are two main causes and conditions of low testosterone, both of which we've discussed so far in our comprehensive article on testosterone.
These are male menopause and hypogonadism. Male menopause is defined as describing a condition in men (primarily middle-aged and older men) that suffers from an age-related decline in adequate endogenous testosterone production.
Hypogonadism is defined as the condition of inappropriate and insufficient production of endogenous testosterone by the testes in individuals of any age and can be caused by genetics, physical injury, disease, or a number of other causes.
Male andropause is a form of hypogonadism because it is a condition of low testosterone.
However, male menopause is a subcategory that specifically refers to the age-related decline in testosterone.
It's a well-known fact that serum testosterone levels decline as men age.
What's interesting, however, is that LH levels remain largely unchanged while testosterone levels decline, and low testosterone levels are associated with negative changes in body composition, energy levels, strength and mass, sexual, physical, and cognitive function, and mood [1].
The same study that confirmed this also demonstrates that age-related low testosterone in the presence of increased or unchanged serum testosterone levels is the result of aging Leydig cells in the testes.
Leydig cells become desensitized to LH stimulation due to the aging process, resulting in a significantly reduced response to LH.
This is one of the causes, and perhaps the most common cause, of low testosterone levels in men going through andropause.
It's also one of the reasons why various treatments for specific causes of low testosterone don't work (we'll get to that in a moment).
In any case, it is very clear that the frailty that is common in aging men is due to this decrease in endogenous androgens, and since it is well known that a decrease in testosterone is a major cause of sarcopenia (loss of muscle mass and strength), TRT (testosterone replacement therapy) has been proposed as a treatment for this [2].
These signs and symptoms of low testosterone occur regardless of the cause, whether it's male menopause or generalized hypogonadism. As mentioned above, symptoms of low testosterone include
- Sexual dysfunction (loss of libido and sex drive, erectile dysfunction, fewer erections)
- Fatigue
- Thinning of the skin
- Decreased muscle mass and strength (sarcopenia)
- Increased body fat
- Negative mood changes (increased depression and negative thoughts)
- Low motivation
- Low energy
- Mood swings
The health complications and risks of low testosterone can also be quite concerning.
While it goes without saying that frailty issues and all the signs and symptoms we've listed so far can be considered risks and health complications in and of themselves, there are a number of well-documented examples of health risks from low testosterone.
These include anemia[3], chronic fatigue[4], osteoporosis[5], diabetes[6][7], cardiovascular disease and chronic heart failure[8], mental/psychological problems including depression[9], and the beginning of evidence for the development of dementia[10].
However, it's interesting to note that treatments for low testosterone, and specifically male menopause, are conflicting.
Despite the fact that male menopause is becoming an increasingly common condition, people with generalized hypogonadism due to a variety of other causes are much more likely to receive definitive treatment, as opposed to age-related low testosterone (male menopause).
While not all medical professionals still fully recognize andropause as a condition requiring treatment, awareness and treatment of this condition is becoming more and more widely accepted and widespread.
In any case, acceptance of andropause and its treatment is now more widespread in the United States, Europe, Asia, and other parts of the world [11].
In any case, determining low testosterone always requires a thorough examination of the patient.
Your doctor will want to rule out all other possible explanations for the various symptoms described above before attributing them to low testosterone.
It is important for individuals to first recognize the signs and symptoms of low testosterone, which typically occur to varying degrees.
Proper consultation with a medical professional is then necessary, including appropriate testing procedures, including blood tests, to determine exactly whether the symptoms are indeed due to low testosterone.
Appropriate treatment can then be applied.
It is also important for all individuals to remember that TRT is generally not a temporary treatment/therapy, but a lifelong therapy that requires a steady dose of testosterone for the rest of one's life.
Anyone considering TRT should keep this in mind.
The long-term safety of testosterone replacement therapy is well documented in all aspects, and in particular, prostate health examinations of TRT patients have confirmed that the risk of prostate-related problems, which has been a common concern for those curious about TRT, is no greater in TRT patients than in the general population [12].
Common treatments for low testosterone, vital marker monitoring, and long-term TRT considerations
Common treatments for all forms of low testosterone can vary, but can generally be narrowed down to two main treatments (in no particular order)
1. testosterone replacement therapy (TRT)
2. attempting to restore HPTA with testosterone-stimulating compounds
1.Testosterone Replacement Therapy (TRT):
The first treatment already discussed in considerable depth in this comprehensive testosterone profile, TRT is probably the most widely used treatment and will therefore be covered first.
While there is no set treatment protocol for low testosterone, TRT is usually the first treatment that a healthcare professional will implement.
However, it stands to reason that attempts to restore the patient's endogenous testosterone production and HPTA function should be the first approach before exogenous testosterone is administered.
While this is becoming an increasingly popular low testosterone treatment protocol among physicians, it has not yet become popular enough for the majority to adopt this two-step treatment approach.
For now, TRT is the first treatment, and as such, we will cover it first.
The administration of exogenous testosterone is typically aimed at a dose that mimics the body's normal physiologic range, which is around 50 to 70 mg of testosterone per week.
In these cases, it is often sufficient to administer a long-esterified variant of testosterone, such as testosterone cypionate or enanthate, at a dose of 100 mg once per week.
Taking into account the weight of the ester and the potential for wastage, the resulting amount is usually within the physiologic range.
Other forms of application, such as transdermal gels (Androgel), are typically prescribed for topical application of 5 to 10 mg daily, which equates to 35 to 70 mg per week.
Of course, all application types can be adjusted based on the judgment and decisions of the patient and doctor.
Typically, this will include input and feelings from the patient about how they are feeling during treatment, and will be followed up with blood tests to really monitor the plasma levels of testosterone.
Blood testing during any kind of TRT course should include consistent monitoring of a full panel of hormones, and this should always include, at a minimum, testosterone:
- Total testosterone levels
- Free testosterone levels
- Sex hormone binding globulin (SHBG) levels
- Estrogen levels (especially estradiol)
- Complete thyroid panel (T3, T4, and TSH - thyroid stimulating hormone)
- Liver function (bilirubin, alkaline phosphatase, aspartate aminotransferase (formerly known as SGOT), and alanine aminotransferase (formerly known as SGPT))
- Total cholesterol - HDL and LDL
- Prostate-specific antigen (PSA)
These are typically the most essential blood levels to monitor for individuals on TRT.
Most doctors who understand proper TRT will already have these tests and functions covered.
Additional levels that should be tested during blood work are usually covered as well, but the levels listed above are the most essential.
Total testosterone levels are the most important because the patient and doctor need to understand where the current exogenous testosterone dosage form is placing testosterone levels, followed by how much of the testosterone is actually free and how much is bound to SHBG.
After that, estrogen levels are the second most important factor to monitor, because many people are using TRT doses of testosterone but can succumb to elevated estrogen levels, which can be indicative of estrogenic side effects.
In these cases, it may be necessary to use a lower dose of an aromatase inhibitor or adjust the testosterone dose to a lower dose.
Although usually used on the recommendation of a physician, most TRT patients may end up using Aromasin (Exemestane) or Arimidex (Anastrozole), one of two aromatase inhibitors used in moderate doses to control estrogen if aromatization issues occur during TRT.
Letrozole (Femara) is not commonly used due to its unrealistically strong properties.
Following these important markers, liver function, cholesterol and PSA levels are important to monitor as these are potentially the ones that testosterone administration can actually affect and change.
Therefore, blood tests should be performed every two months, and all should be monitored at an approximate frequency throughout the duration of TRT administration.
One final important point when considering TRT is the fact of Leydig cell atrophy in the testes.
While it is well understood that TRT is a lifelong treatment, there may be male patients who wish to discontinue TRT at any point in their lives for any reason.
Other patients may want to avoid testicular atrophy while on TRT, despite the long-term, lifelong treatment. One of the most common questions asked by TRT patients is "How can I avoid testicular atrophy during testosterone replacement therapy?".
The answer lies in the regular use of human chorionic gonadotropin (HCG).
HCG is a gonadotropin derived from the urine of pregnant women, but interestingly, it contains structurally identical components to LH (luteinizing hormone).
As such, it acts in the testes of men in the same way as LH in the human body, stimulating Leydig cells to start or continue testosterone production, thus avoiding prolonged Leydig cell and testicular atrophy.
There are a myriad of protocols for periodic administration of HCG during TRT, but the general concept is to administer HCG frequently (approximately 500-1000iu every two to three days for a total of one to two weeks) to maintain testicular size and function.
2. Attempting to restore HPTA with testosterone stimulating compounds:
This is a lesser-known and less-tried treatment, but should be utilized more frequently and earlier before exogenous testosterone is used for TRT for the rest of the patient's life.
However, as mentioned earlier, the majority of TRT patients with low testosterone levels are said to have andropause, which is the result of Leydig cell aging rather than a decrease in LH secretion from the pituitary gland.
Therefore, the only way to treat low testosterone in these cases is to use exogenous testosterone for the purpose of testosterone replacement therapy.
For example, if testosterone is low due to decreased LH and FSH production, which is common in patients with anabolic steroid-induced hypogonadism (ASIH), the first treatment is usually an attempt to restore HPTA through testosterone-stimulating compounds.
It is very well known that there is a widespread suppression of serum gonadotropins and consequently testosterone levels following anabolic steroid use, which typically persists indefinitely after anabolic steroid use is terminated [13] [14] [15].
The problem with administering HCG alone or putting patients with this type of low testosterone on TRT is that both of these treatments must be administered continuously for life and the body's endogenous production is not self-sustaining without outside help.
Combination treatments using a combination of aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and HCG are commonly utilized to attempt to restore HPTA function without the need for lifelong TRT.
If these therapies are not successful, TRT is then typically used as a second line of treatment.
Aromatase inhibitors, in particular, have been shown in many studies to increase the gonadotropins LH and FSH, and consequently total serum testosterone levels [16].
Because of their estrogen antagonism to the pituitary gland and consequent increase in testosterone production by Leydig cells in the testes, SERMs are actually frequently used in the medical community as a treatment for HPTA recovery [17] [18] [19] [20] [21].
While the standard treatment for low testosterone is TRT, a growing number of medical professionals are continuing to adopt the use of endogenous testosterone stimulants as described earlier to treat patients with low testosterone who do not exhibit Leydig cell insufficiency due to the aging process [22].
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