Male hypogonadism is a disease that one associates with decrease in the functionality of testes. That is, either the sperm production in the body is on a low or the testosterone production is less. There are two types of hypogonadism, primary and secondary. The primary one is a result of some disease of the testes. The secondary one, on the other hand, occurs from a disease of hypothalamus or pituitary gland. Hypogonadism is also commonly referred to as Low T.

Testosterone action: What are the mechanisms?

Testosterone has multiple biological effects. This is mainly because testosterone has the ability to act as three completely different types of hormones.

  1. It can bind to the androgen and act directly.
  2. Testosterone might act inside the tissues that have the enzyme 5-alpha-reductase.
  3. It can also acts as an estrogen after converting from aromatase to estradiol that further binds to the estrogen receptor.

It is essential for the testosterone to convert to dihydrotestosterone for it to act appropriately on the external genetelia as well as sexual hair. This particular mechanism is responsible for providing the reason for utilizing the 5-alpha-reductase inhibitor. Also, for using the finasteride in order to treat benign enlargement of the prostate and male pattern baldness that occurs.

To act upon the bone, it is essential for testosterone to convert to estradiol. This is essential because of a fairly rare condition of the aromatase deficiency that occurs in men. This deficiency further results in epiphyseal closure failure as well as severe osteoporosis.

It is essential for testosterone to convert to estradiol for another reason too. It is essential so as to regulate the sexual function of the body and reduce the body fat in men, too. This was evident from an experiment in which various men in the age of 20 to 50 years were getting treatment with a gonadotropin-releasing hormone (GnRH). They were receiving this treatment to supress the secretion of testosterone and estradiol in the body. After this, it was replaced with just testosterone with/ without an aromatase inhibitor. 

Principles behind testosterone therapy

The key principles involved are as follows:

  • Only a person having hypogonadism or Low T, as some call it, should get testosterone therapy. Also, there should be proper clinical evidence of it depending upon the systems and other signs that show clear androgen deficiency as well as a subnormal serum testosterone concentration.

It is crucial to understand that a man who is showing an increase in the serum testosterone concentration and is having symptoms of Low T will not show any relief in those suggestive symptoms.

 

  • The symptoms that indicate androgen deficiency are low Bone Mineral Density (BMD), lesser morning erections, low level of libido and loss of body hair too. In addition to these symptoms, the person also shows signs of depression, anaemia, lesser muscular strength, etc.

 

  • Irrespective of the cause of testosterone deficiency, that is whether it is primary or secondary, testosterone can be replaced.

 

  • The main aim of testosterone therapy is to get the serum testosterone concentration level back to normal again.

 

  • Also, testosterone therapy is a treatment only for the case in of reduction in serum testosterone concentration that is a result of increasing frequency in men who are older in age, that is, above 60 years.

 

  • This therapy is useful in case of testosterone deficiency only. It does not play a significant or beneficial role in case of spermatogenesis. Rather, testosterone therapy further impairs the spermatogenesis by suppressing pituitary gonadotropin secretion.

 

What are the benefits of testosterone therapy for men who have hypogonadism?

Testosterone therapy shows desirable effects in men who suffer from Low T. The most significant ones include increase or proper maintenance of the secondary sexual characteristics. Also, it shows an increase in libido, an improvement in muscle strength and better bone density too.

 

  • Virilization/sexual function

When the serum testosterone concentration comes within a normal range, it leads to normal virilization in case of men who are non-virilized. Also, it leads to virilization in those men who are already virilization.

 

  • Muscle strength/fat-free mass

The replacement of testosterone also leads to great improvement in the muscular strength as well as fat-free mass in men suffering from Low T. One of the reports showed that the administration of 100 mg of testosterone enanthate once a week for 10 weeks to hypogonadal men resulted in an increase in their strength in the bench press by about 22 percent. It also enhanced their squat strength by around 45 percent, as well as their fat-free mass by 5 percent.

 

  • Bone density

A study was conducted on 72 men who were suffering from male hypogonadism and were undergoing testosterone therapy as well. They showed significant improvement in their bone density. Initially, in the first year of treatment, bone density, on and average was maintained at about 39 percent. It further lead to normal range slowly in the consecutive years.

 

There are a few other effects too. However, these have not been proved very convincingly. The most significant ones out of these are:

 

  • Mood

Men who sever from Low T moderately to severely showed improvement in moods when treated with testosterone therapy. After a treatment of about 30 weeks, there were significant improvements in the mood of the men undergoing the treatment. However, there was no control or binding on this study. There are a few more studies as well that suggest that testosterone therapy showed improvement in the persons’ moods as well.

 

  • Cognition

There were not very significant changes in cognition when men who are older in age who have low testosterone concentrations were observed.

 

It is essential to understand that the time course of the effects of testosterone therapy are highly varied. Several studies have been conducted and many of them show different outcomes. Therefore, it is safer to say that there are variations in the outcomes of testosterone replacement. Also, one can observe the effects at different times.

Those who are receiving treatment show enhancement in fat-free mass, erythropoiesis, prostate volume as well as better sexual function. These effects were mainly observable in the initial three to six months of treatment. In comparison, an effect on the Bone Mineral Density (BMD) was observable much later, after about 24 months.

 

What is the approach to treatment?

Appropriate candidates – Hypogonadal adult men

There should be administration of testosterone only to those adult males who have hypogonadism or Low T. Also, this should have proper evidence through clinical symptoms as well as signs that are consistent with respect to androgen deficiency and a subnormal morning (that is, 8:00 to 10:00 am) serum testosterone concentration on three separate occasions.

The ideal scenario is to take the samples when one is in fasting mode. There are a number of signs as well as symptoms that indicate low levels of libido, androgen deficiency, low BMD, small testes, and other suggestive symptoms. On the other hand, the symptoms like anaemia, depression, fatigue, etc. are not that prominent.

In case of males who are older in age and show symptoms of Low T, testosterone replacement helps them in the treatment of low serum testosterone concentration that is a result of old age. There are clear proofs that show that testosterone has positive effects on mood, physical as well as sexual function.

Testosterone therapy has been inappropriately used as well. The main reason for this is DTCA, or Direst To Consumer Advertising that encourages men to utilize testosterone products by relating it to absurd issues such as reduced interest in sexual activities and energy. It is highly essential that the clinicians understand that this is not the right way. If one wished to take any such treatment, proper medical diagnosis for testosterone deficiency is crucial.

There could be men who show symptoms that are quite vague, example- mood changes of fatigue. These symptoms should not be associated with testosterone deficiency without clinical diagnosis. It is not a wise idea to prescribe this treatment on a ‘trial basis’ to simply check the effects of it on the males showing symptoms. Moreover, over a period, testosterone therapy can lead to suppression of spermatogenesis and a reduction in the testicular size.

 

Which testosterone regimen to choose?

There is proper knowledge and understanding of pharmacokinetics is crucial when it comes to picking one of the different testosterone preparations available. The absorption of native testosterone is much better from the intestine. However, it is metabolized in such as quick way by the liver that it is highly difficult virtually to maintain serum testosterone concentration in a normal range in a man suffering from Low T with oral testosterone. Over the years, there have been multiple solutions. These involve modification of the testosterone molecule, altering the way of testosterone delivery, or even both.

One of the best suggestions would be to opt for testosterone gels. This is due to the fact that they typically result in serum testosterone concentrations that are in normal range and stable as well. Also, most patients as well prefer gels as compared to to other preparations. However, there are various other factors that are to be taken in consideration when it comes to choice of regimen, including patient preference, cost, convenience, and insurance coverage. All these things vary according to the plan and regimen that is selected. In comparison, the cost of the gels is the highest.

Oral preparations, that is, multiple types of 17-alpha alkylated androgens have existed in the market for oral use for several years. One of the most common examples of this would be methyltestosterone. However, it is not a healthy choice to opt for. Several years ago, research was conducted and multiple investigators suggested that addition of an alkyl group in the 17-alpha position of the testosterone molecule reduced its catabolism by the liver.

In fact, there are many endocrinologists who provide treatment for male hypogonadism have a notion that oral preparations are not completely effective when it comes to production of virilization. As of now, there are no such studies have tested these suggestions made by them.

Also, multiple reports indicate of hepatic side effects with oral preparations. These include a hepatic cystic disease called peliosis hepatis, cholestatic jaundice, as well as hepatoma. For these particular reasons, it is better to not make use of 17-alpha alkylated androgens to treat testosterone deficiency.

Oral testosterone undecanoate is also available in certain countries. However, it is not available in the United States.

 

Parenteral testosterone

There are long-acting injections. Testosterone enanthate and testosterone cypionate are actually esters of testosterone. In this treatment, esterification of a lipophilic fatty acid to the 17-beta hydroxyl group of testosterone id done. This results in testosterone that is further more lipophilic in comparison to the native molecule. There are various other results of it as well. The Intramuscular (IM) injection of testosterone esters further leads to their storage in, as well as gradual release from the oil-based vehicle. This basically prolongs the presence of testosterone in the blood.

In comparison, the therapeutic characteristics in the case of testosterone enanthate are well described.

There are several experiments that show that the serum concentrations of luteinizing hormone (LH), that were above normal in all of the men in the initial stage. They show reduction in numbers gradually after initiation of the 100 mg/week regimen. In about 6-8 weeks, it reached the normal range. Also, serum LH concentrations showed reduction too with the 200 mg per two-week regimen.

There is not much valid information that one can find for testosterone cypionate. However, there are a lot of studies and research papers on the topic. These studies suggest that its characteristics are very similar to those of testosterone enanthate.

One of the major benefits of testosterone enanthate and cypionate when it comes to comparing with other testosterone preparations is that these are biologically much more effective in both initiation as well as maintenance of normal virilization in all the males who are suffering from hypogonadism. Also, for some men, one more advantage is there that there is no need for daily administration in this method. There are some disadvantages too. There is a need for deep IM administration of an oily solution every 1-3 weeks as well as one can observe fluctuations in the serum testosterone concentration. These fluctuations further result in fluctuations in energy, mood, as well as libido in many patients. These fluctuations are more prominent as the provider gradually increases the dosing interval.

The manufacturers present in countries other than the US suggest a dosage of 1000 mg administration as a deep IM injection. After this, the patient gets the second dosage after six weeks of the first one. Then, the subsequent administration of doses is essential once in every 10-14 weeks. Also, several studies show that consumption of 1000 mg in every 3 months helps in maintenance of serum testosterone concentration within the normal range. This takes about 18 months.

In United States, however, the dosage preparation is quite different. Every dosage is 750 mg that is injected with 3 ml of oil only into the buttocks. Also, after the initial dosage, the patient gets the second dose after four weeks. Later, the patient gets subsequent doses in every  10 weeks.

In the States, there is restriction on the availability of this drug. It is only available through a program popular as the AVEED Risk Evaluation and Mitigation Strategy (REMS) Program. It is essential for all the injections to get administration either in a hospital or in an office. It is the health provider who has training and experience who handles the administration. Also, proper monitoring is a must later for 30 minutes for any kind of adverse reactions.

After the third injection dosage, the average serum testosterone value occurs almost after a week.

It is essential that one confirms proper diagnosis for hypogonadism using clinical methods . Even if the symptoms and signs are evident without any test, confirmation is a must. Only after proper medical reports that suggest that the male is suffering from Low T, proper treatment should be given. Also, it is essential to administer the effects after giving the dosages as each patient might react differently to it. Proper monitoring is crucial.

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Testosterone replacement therapy or TRT has become a widely used form of therapy for hypogonadal men or older men who have abnormally low testosterone levels. Recently, it has found a growing following because of its  success in boosting testosterone levels as well as energy and sex drive. People also claim that it has helped them lose body fat and increase muscle mass. When a male reaches the age of 35, he starts to experience a reduction in testosterone production (around 1% each year) which results in low testosterone or Low T. This results in reduced libido, fast energy depletion, and reduced bone density and muscles.  Despite its amazing benefits and surging popularity, TRT remains a controversial treatment because of its potential health risks. Before we go over the health risks, let’s first understand how the testosterone serum is administered and monitored.

Standard Monitoring Procedure

Testosterone therapy is a therapy that should be considered only for men with low testosterone levels and clinical symptoms of hypogonadism. Hypogonadism is a condition where the testes fail to secrete hormones which decreases sperm production resulting in infertility. Male testosterone level peaks during the age of 20 and slowly decreases per year. Doctors suggest testosterone monitoring should start at age 35 and should be checked every five years. Men with low testosterone experience a decline in physical energy, strength, stamina, and mental aggressiveness. They also experience more aches and pains in bones and joints and have a decline in libido and erections. Some also experience weight gain and osteoporosis. 

For the last three years, the guidelines for monitoring testosterone has changed dramatically, as physicians highlight the importance of proper diagnostic process and monitoring plan. Once a man starts testosterone therapy he has to be closely monitored to make sure his testosterone levels don’t become too high as this may have negative side effects. Making sure that testosterone levels are balanced is important throughout the procedure. During the therapy, patients are checked to determine their levels of serum testosterone concentration. Due to circadian variations in testosterone levels, it is highly recommended to do the measurement in the morning. 

Before treatment, men should undergo a digital rectal examination or DRE and PSA.  This is to prevent accelerating tumor growth for men with prostate cancer. To be safe, it is recommended to have a digital rectal examination and check the PSA level before undergoing testosterone replacement (especially for adult men over the age of 40 with a family history of prostate cancer). All kinds of prostate conditions should be treated first before the initiation of testosterone replacement.    

From two to three months until normal serum testosterone concentrations are achieved, the patient should be monitored and assessed to see if symptoms have improved. When the dose remains stable, monitoring is changed to every 6 to 12 months. 

Testosterone serums are masured between injections who are receiving enanthate or cypionate, with a value ranging from 500 to 600 ng/dL ((17.3 to 20.8 nmol/L). Dosage should be decreased if results show more than high values.  Overall, the goal here is for the patient to have a normal testosterone value from 400 to 700 dL. 

Benefits of a High Testosterone Level 

Men with higher than average testosterone level experience the benefits of a normal blood pressure and lower likelihood of obesity and heart attack. Good testosterone levels also results in a healthy heart that pumps blood to the rest of the body. A healthy testosterone level also means better libido and sex drive. Testosterone also helps red blood cells production which lowers the risk of various cardiovascular diseases. 

Men who have high testosterone also have increased muscle mass. They have higher muscle size and strength as well as stronger bones. A male with high testosterone also has increased brain function with improvement in spatial memory and reduced risk for Alzheimer’s during old age. 

Potential Side Effects of Testosterone 

TRT is often marketed as a solution to fatigue, low sex drive, depression, and other ailments related to aging. It has a lot of benefits for patients seeking a better quality of life and reducing the negative effects of aging. However, there may be potential effects that can range from mild to undesirable. Therefore, those who are considering the treatment should know beforehand the uncertainty and long-term safety of the procedure. The patient should also be able to weigh the risks and benefits of the therapy before undergoing it. Here are some of the possible effects of TRT.

Prostate Cancer

Medical science has always been wary about hormonal therapy for cancer.  Despite lack of data suggesting testosterone treatment can increase the risk of prostate cancer, many physicians still believe that prostate cancer can be stimulated by testosterone which is why TRT is contraindicated for patients with  suspected prostate cancer cases. Rare cases found that testosterone can increase the growth of the tumor or benign prostatic hyperplasia for people that aren’t hypogonadal. If you’re at high risk for prostate cancer, take a cautionary measure first before approaching the therapy. 

Obstructive Sleep Apnea

Men who already have obstructive sleep apnea (OSA) can experience a worsening of their condition. Sleep apnea is described by excessive daytime sleepiness. Low T and aging can also be directly influenced by sleep deprivation, which is why treatment of OSA is also known as cure for hypogonadism and decreased sexual function.  

Patients who are treating their OSA with CPAP can take testosterone treatment. However, severe OSA should not be treated with TRT. This is due to the morphologic and neuromuscular changes to the airways of a person with extreme OSA.

Erythrocytosis

Another potential side effect of testosterone injection is the condition called erythrocytosis. Erythrocytosis is described as the increase in RBC mass usually linked to increased hematocrit of more than 54% (HCT) and hemoglobin concentration. Before undergoing testosterone treatment, men should have a complete blood count that has to be monitored over the course of the therapy. Also, the hematocrit should first be measured, and to be repeated after three to six months, and then annually. 

In cases where polycythemia occurs during treatment, a cessation of therapy or lowering of dose is advised. This is to prevent the risk of myocardial infarction, stroke, and venous thromboembolism.

Venous Thromboembolism

Testosterone products in the US often used to have a warning sign about the risk of venous thromboembolism or VTE (caused by erythrocytosis, as mentioned above). However, this is now brought replaced with a more general warning as more studies show that VTE isn’t associated with men taking testosterone. Screening for thrombophilias is therefore not suggested for men considering testosterone therapy.

Cardiovascular Diseases 

Men who have been using TRT for several months have been found to have a high risk of cardiovascular problems like heart attack and stroke. In 2015, the FDA and the Endocrine Society has already made statements about the potential side effects of testosterone therapy to patient’s cardiovascular system. They added warning to drug labels due to the  numerous data and studies of testosterone use leading to decline in cardiovascular health and increased incidence of CV death in men abusing steroids.

Skin Irritation 

Testosterone patches like the androderm has been reported to cause skin rashes ranging from mild to severe. Gels have also been reported to transfer irritation from person to another but the possibility is low and can be prevented by a simple pre-treatment of corticosteroid cream. This patch has been banned from the market in some countries. Irritation and exposure can be avoided by washing hands as well as avoiding skin contact and water exposure for the first five hours after application. 

Summary and Recommendations 

Hormonal treatment is still a new form of medication, so a cautious approach is still the safest path if you’re interested in testosterone therapy. Before going into therapy ask yourself other factors that may be causing your fatigue, low sex drive, and mental decline? Rule out other issues such as relationship and psychological problems first before reaching out for another solution.

  • The primary objective of TRT in hypogonadal men is to restore normal levels of testosterone. 
  • Gels and other transdermal testosterone treatments are highly recommended for most patients. Injections are good for long time users and those who don’t want to apply them daily. 
  • Men who begin therapy must have their testosterones measured two to three months after to evaluate and reduce undesirable effects. 
  • Men over the year of 40 should be screened for prostate cancer prior treatment.
  • Hematocrit should be measured and evaluated before and after therapy.
  • Testosterone treatment should only be for men who experience undesirable effects of low T more than once. 
  • Bone loss and bone density reduction is one of the known symptoms of hypogonadism. If problems in the bones were present, a bone density test should be reassessed every two years until the hormones are stabilized or brought to normal. If the hormones stabilizes and patient is still experiencing bone decline, treatment for osteoporosis must be initiated.
  • Be careful when choosing your doctor to assess your test result. A false diagnosis of low T can be dangerous to your health. Testosterone should be measured in the morning between 7 and 10 am.