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TESTOSTERONE TREATMENT FOR MALE HYPOGONADISM

Male hypogonadism is a condition characterized by the impairment of either of the two primary functions of the testes: sperm or testosterone production. Testosterone plays a crucial part in masculine growth and development during puberty. 

There are two types of hypogonadism. The first one is called “primary hypogonadism” or testicular failure and is caused by impairment in the testicles. The second one, called “secondary hypogonadism” is caused by a problem in the hypothalamus—the part of our brain which signals the testicles to produce testosterone. 

 Hypogonadism is a disease which a person can get from birth or develop later in life from infection or injury. Treatment will depend primarily on the cause and stage of life where hypogonadism has affected the patient. Adult men who have hypogonadism can experience loss of function in reproductive organs which often results in decreased energy, sex drive, and depression. When ignored and untreated, it can lead to serious conditions such as infertility and erectile dysfunction. It can also cause mental and emotional changes such as loss in focus and. 

Finding the cause of hypogonadism is crucial in successful treatment and recovery. Most male hypogonadism can be treated with testosterone replacement therapy. 

Mechanisms 

Testosterone is needed by male germ cells for their maturation period. It’s also an important hormone for sperm production and male fertility. Overall, the testosterone is the primary male sex hormone in mammals, primates, bull sharks, birds, and other vertebrates. 

At age 12-16, testosterone is needed in order to initiate sperm production and stimulation of sexual behavior. For adult males, testosterone is needed to improve red blood cell production, maintain muscle mass, strength, libido, and spermatogenesis. Testosterone circulates in three major forms: unbound, testosterone, and tightly bound testosterone. Only the free and the weakly bound testosterone is available to bind to an androgen receptor. In males, serum testosterone levels vary and are supposedly highest in the morning and lowest in the late afternoon. Young men have a testosterone level average of 35% in which the total range for a normal healthy adult is 300 ng/dL to 1000 ng/dL.

Testosterone can act as three hormones and has several effects on our bodies. First, it can function by simply binding to the androgen receptor. Testosterones can also function in tissues that express the enzyme 5-alpha reductase via conversation to dihydrotestosterone which can also bind to androgen receptors. Lastly, it can act as estrogen through conversion by aromatase to estradiol which then binds to the estrogen receptor.  

Testosterone needs to be converted to dihydrotestosterone in order to function on the external genitalia, prostate gland, and sexual hair. This mechanism for potent androgen dihydrotestosterone (DHT) provides the basis for treatment in prostatic enlargement. While in the prostate gland, the type II 5-alpha-reductase metabolizes testosterone into DHT which can work.


When we think about estrogen and testosterone, we assume that testosterone = men, estrogen = women. However, estradiol, which is a form of estrogen also has an important role in male sexual function. Testosterone also needs to be converted to estradiol to work on bones. Estradiol is also important for balancing libido, erectile function, and sperm production. Estrogen receptors are needed in order to convert testosterone to estrogen. These receptors can be found in the testis, penis, brain, and all other organs working during sexual arousal.  

This is why most males with low testosterone but elevated estrogen can have a higher risk for erectile dysfunction. In order to prevent this, the regulation of testicular cells through the help of estradiol is important. Other benefits of estradiol include a decrease in body fat and normal sexual function in men from 20-50 years old.

Guidelines

Testosterone therapy has been a highly disputed form of treatment for men because of the lack of data about its long-term outcome. However, prescriptions for testosterone are becoming more and more common now in public as more studies shed light on its effectiveness. From treating sexual dysfunction in men to improving libido, bone mass, and overall health—testosterone treatment is gradually earning the public’s trust. When it comes to testosterone therapy, there are a few guidelines to follow for success. 

  • The therapy should be considered only for men with low testosterone levels or those who show clinical symptoms of hypogonadism (ex. sexual dysfunction). Before treatment, males should be measured for their morning testosterone levels. It should be during the mornings for it is when testosterones are at their peak level. 
  • Increasing the serum testosterone for men who already have normal testosterone concentration will not provide any relief for any hypogonadism symptoms such as low libido, loss of body hair, and low bone mineral density. 
  • Testosterone therapy is effective whether testosterone deficiency is due to primary or secondary hypogonadism.
  • The objective of testosterone therapy is to restore serum testosterone concentration to normal range. It is to treat decline in testosterone which occurs in men above the age of 60. For hypogonadal men, this can improve sexual function, energy, mood, and muscle mass. The development for libido usually occurs 6 weeks of treatment whereas other benefits may take up to 12 months. 
  • The therapy can only cure testosterone deficiency not impaired spermatogenesis. Testosterone therapy can further cause problems by suppressing pituitary gonadotropin secretion. 

Clinical Benefits

Below is an in-depth review of the clinical benefits of testosterone therapy

Improved Sexual Function

Erectile dysfunction is a condition that increases with age. Testosterone therapy increases the testosterone levels of men in order to prevent effects of low-T and increase sexual function. Testosterone therapy has shown positive outcomes for enhancing libido and sexual activity. While transdermal testosterone replacement therapy has shown positive effects in mood, fatigue, and sexual function.  

Successful treatment is also linked to normal virilization in men who aren’t virilized and stability for those who are. Virilization also called “masculinization” is a development stage where sex differences from the female become more recognizable in the male body. This happens during puberty but in cases where hypogonadal adult men didn’t have normal virilization, hypogonadism is often manifested by a decrease in libido and energy. 

Muscle Strength/Fat-Free Mass

Loss of lean body mass and muscle strength are the two most common effects of hypogonadism. This is also linked with obesity and high levels of blood fats which increases the risk for certain diseases such as diabetes, cardiovascular conditions, and depression. Testosterone therapy has proven effective in increasing muscle strength and fat-free mass for men with hypogonadism. In a recent report, researchers have found that 100mg of testosterone enanthate a week for several consecutive weeks increased muscle strength in bench press by 22 percent, squat strength by 45, and fat-free mass by 5 percent. 

Bone Density

Bone mineral density decrease is also a major symptom of hypogonadism. While there are numerous studies of osteoporosis in women, studies focused on bone mineral density in men are only a few which makes it hard to know the long-term effects testosterone on hypogonadal men. However, of these few studies, it shows that when hypogonadal men are treated with testosterone, their bone mineral density increases. The increase averaged to about 39 percent in the first year of treatment and was most effective to those with lowest bone density measurements. 

Mood and Cognition

Therapies that prevent and slow the progression of Alzheimer’s diseases has been a hot topic for years. Hormonal therapies such as testosterone therapy are one of them. Testosterone therapy has long been believed to also improve cognition and mood, however, the long-term effects of the therapy are not studied well enough to support a strong conclusion. Also, data on the association of the therapy and mood prove inconsistent. One study proves that testosterone levels have a direct link to spatial cognitive function and memory as well as visual stimuli for older men. It is known that the male brain converts testosterone to estrogen by aromatase enzymes, therefore, researchers believe testosterone can also affect cognition by conversion to estrogen.

General Approach to Treatment

Hypogonadism diagnosis should only be done for men with symptoms and those who show consistent signs of Low T and consistently low serum T concentrations. It is recommended that T concentrations should be measured using an accurate and reliable assay. Diagnosis should be confirmed by repeating the measurement of morning (8 to 10 AM) serum testosterone concentration three times on separate days. It is also imperative that samples should be taken before fasting. 

For men with a less normal range of total T who have conditions that alter sex hormones, it’s recommended to obtain a free T concentration using equilibrium dialysis or estimating using an accurate formula. For men with androgen deficiency, it is recommended that you have an additional diagnostic evaluation for the cause of androgen deficiency. 

Symptoms and signs of androgen deficiency include low sex drive, decreased morning erection, reduction of body hair, and low bone mineral density (BMD), gynecomastia, and small testes. Symptoms such as anemia, depression, reduced muscle strength, and increased fat mass are also considered but are less specific. 

For older men with low T and symptoms of hypogonadism, testosterone replacement therapy can increase sexual function, mood, and physical function. However, healthy middle-aged men who use testosterone therapy shouldn’t be encouraged. It’s important that doctors understand that testosterone deficiency should only be diagnosed based on a clinical symptom and consistent low T. The use of testosterone for these vague cases are strictly discouraged and should not be prescribed on a “trial” basis. Serious side effects such as suppression of spermatogenesis and decreased testicular size is found in men who abuse testosterone. 

A Review of Testosterone Therapy Preparations 

There are different ways to administer testosterone therapy but all of them require an understanding of their pharmacokinetics. While native testosterone is absorbed by our intestines quite well, it is found that the liver metabolizes it rather rapidly which makes it hard to maintain a normal serum testosterone concentration in a hypogonadal man. Oral formulas are also linked to liver toxicity and fluctuations in testosterone levels. Years ago when they were still available, many people have been using oral forms of testosterone which resulted in various hepatic cystic diseases including peliosis hepatis and hepatoma. For these reasons, oral testosterones are discouraged by many endocrinologists and are now unavailable in the United States. 

Over the years, this problem has been given a solution through different ways such as the modification of the testosterone molecule, method of delivery, or both. Today, there are several testosterone preparations that are currently USA FDA approved. The most common and highly suggested are the testosterone gels.They provide normal and relatively stable serum testosterone concentration for most patients. They are also preferred most because they are often covered in most insurances. Other preparations such as patches and injectables are cheaper. 

Parenteral Testosterone 

Parenteral testosterone supplementations are common methods of treatment for hypogonodal men.

Long acting injections


Long-acting injections are a new formulation for therapy of testosterone deficiency. It is done by administering 100mg of testosterone enanthate once a week for 12 weeks. Administration can also vary based on testosterone serum levels and individualized therapy can also shorten or prolong the intervals. 

Available data on this form of preparation suggests that most men can do this treatment once every 1-2 weeks, a few can do it once every three weeks, but not once every four weeks. Thus, our recommendation rests to 50 to 100mg every week or around 100 to 200 mg every two weeks. The advantage of long-acting injections is that it’s effective in maintaining virilization in hypogonadal men. It’s also preferred for freedom from daily injections. 

Extra-long acting injections 


Extra-long acting injections are types of preparation which recommends a dose of 1000mg administered as a deep IM injection. The second dose is done six weeks after the first and a subsequent dose is administered every 10-14 weeks. 

Studies have shown that  1000 mg every 3 months can already maintain the mean serum testosterone of an individual for the range of 18 months. Dosing for US preparations are a bit different as each dose has around 750mg in 3mL of oil administered through the buttocks. After the first dose, a second dose is done four weeks later and subsequent doses every 10 weeks. 

Side effects are minimal with rare cases of pulmonary oil microembolism and anaphylaxis. The drug is heavily restricted and can only be attained from a program called the AVEED and REMS program. Administering of the drug is only prohibited in a hospital or office setting by a registered or trained health care provider. There’s also strict 30-minute monitoring afterward for adverse reactions.

Based on the data, serum testosterone value after the third injection should occur approximately after one week. It should also follow a decline until the next injection. The concentration at five weeks will then provide an average for the inter-dosing period. This form of preparation is only recommended for patients who do not have access to other forms of testosterone treatment.

Transdermal / Topical Delivery

 Transdermal or topical delivery is a formulation that can be applied to the skin using a metered pump spray.  It was first introduced to the public in 1994 along with the scrotal patch. Since then, gels and body patches have surged in popularity and the scrotal patch became no longer available in the United States. Perhaps the most beneficial property of the transdermal administration is its maintenance of stable serum testosterone concentration. This stability results in positive effects including improved mood, high energy, and libido. Patients treated with transdermal testosterone reported a 75% increase in energy levels and 70% increase in sexual drive. The topical administration is deemed safe and effective for hypogonadal men who have suboptimal responses to previous treatment with gels.

Androderm


An example of a transdermal testosterone patch is Androderm. It is a common treatment for adult males who experience low testosterone due to a medical condition. This patch is designed to deliver 2 or 4mg of testosterone for 24 hours following application to non-genital skin (ex. Upper arm, thighs, back, and abdomen). It results in normal serum testosterone concentrations in the majority of hypogonadal men. However, reports claim that as many as one third who try this preparation are affected by severe skin rash. Other serious side effects of this product include enlargement of prostate gland, and increased urination. Androderm is currently available in the US as well as many other countries but not in the UK. 

Testim


Testim (1% testosterone gel) is an FDA approved testosterone replacement therapy for men associated with deficiency or absence of endogenous testosterone. It is sold in tubes of doses 5 and 10g which contain approximately 50 and 100mg of testosterone. The regular application promises normal serum concentration of testosterone.  

The gel is known for its musk-like odor and translucent color and should be applied on dry skin of shoulders or upper arms 

Fortesta  


Foretests  (2% testosterone gel) is a translucent, odorless gel that contains testosterone. It is sold via a metered-dose pump and each pump provides a total of 10mg of testosterone per container. Expert recommended dose is around 40mg and applied to the inner and front thighs. Application should be adjusted to a minimum of 10mg – 70mg depending on the patient’s determined serum testosterone concentration. 

Axiron


This topical solution is known for its clean and colorless appearance. Each single-phase solution has 30mg of testosterone in 1.5mL of Axiron solution that is administered through the axilla. The package insert starts with a dose of 30mg applied to each axilla with a total of 60mh. The dose can be adjusted for as low as 30 mg to as high as 120mg per day. 

The following are some of the widely available generic versions of gels:

  • Striant SR (30mg) – testosterone buccal used to treat males with low testosterone levels. This tablet is used twice a day and shouldn’t be used for men with prostate or breast cancer. Misuse of this drug can have dangerous and irreversible effects. It shouldn’t be used by a woman or child.

 

  • Testopel (75mg) – are testosterone pellets that contain inactive ingredients such as stearic acid and polyvinylpyrrolidone USP. This kind of treatment allows for the slow release of testosterone and a long acting androgenic effect. Recommended use is three to six 75mg pellets every three to six months and should be implanted in subdermal fat of buttocks, abdominal wall, or thigh. 
  • Natesto – an approved nasal testosterone gel available in the US for treatment of male hypogonadism. It is administered via nostrils using a metered-dose pump applicator. Each pump actuation delivers 5.5 mg of testosterone with a daily recommendation of 33mg/day. 

Human chorionic gonadotropin (hCG)

HCG works by stimulating the testes to make testosterone and sperm. It is administered through IM injection 2-3 times per week. Also known as “the pregnancy hormone”, this hormone plays an important role during pregnancy. HCG injections are also approved by the US Food and Drug Administration to treat medical conditions in men. 

 

Suppression of spermatogenesis


The administration of testosterone exogenously to suppress LH secretion and high concentration of intratesticular testosterone which are vital for spermatogenesis. This replacement therapy affects fertility and should not be considered for men who desire fertility. 

Contraindications to Testosterone Therapy

Testosterone therapy is an effective treatment for hypogonadism but it isn’t without any risk. Like any other medication, testosterone therapy can have adverse effects on the body, especially for those who are undergoing medication or currently suffering from illness. Testosterone replacement therapy has many side effects that may be dangerous for patients with serious medical issues. So who should not take testosterone?

  1. Patients with prostate or breast cancer. Prostate can grow larger under the stimulation of testosterones.
  2. Patients with severe lower urinary tract symptoms (LYTS)
  3. Untreated severe sleep apnea. This condition can be severely worsened by a person taking testosterones.
  4. Patients who desire to have children. 
  5. Patients who have a weak heart. A 2010 study found that men who took testosterone supplements increased in heart problems. Men with congestive heart failures are not advised to take testosterones. 

Testosterone replacement therapy – TRT

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 measured 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 on a patient’s cardiovascular system. They added a warning to drug labels due to the  numerous data and studies of testosterone use leading to a 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.