What is testosterone replacement therapy

Testosterone replacement therapy also called TRT is testosterone therapy for male hypogonadism ¹, ², ³. The indication of testosterone-replacement therapy treatment requires the presence of low testosterone level, and symptoms and signs of low testosterone or hypogonadism ⁴. Hypogonadism is seen in 19% of men in their 60s, 28% of men in their 70s, and 49% of men in their 80s ⁵. Low testosterone (hypogonadism) can be treated with the use of doctor-prescribed testosterone replacement therapy. Testosterone-replacement therapy treatment is safe and can be effective for men who are diagnosed with consistently abnormal low testosterone production and symptoms that are associated with this type of androgen (hormone) deficiency.

Testosterone is US Food and Drug Administration (FDA) approved as replacement therapy in men who have low testosterone levels and those with symptoms of hypogonadism ⁶. It is important to distinguish between primary (testicular) and secondary (pituitary-hypothalamic) hypogonadism. Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, decreased nocturnal penile tumescence, decreased libido, decreased beard growth, and shrinking testicles. The normal range for early morning testosterone in a male is between 300 ng/dL to 1000 ng/dL ⁷.

Testosterone therapy is not FDA-approved to treat low libido in women.

While testosterone replacement therapy is the primary treatment option for men with low testosterone or hypogonadism, some conditions that cause hypogonadism are reversible without testosterone therapy. These should be addressed before testosterone therapy is contemplated. If testosterone therapy is needed, goal of treatment is to improve symptoms associated with testosterone deficiency and maintain sex characteristics. There are many different types of testosterone therapy. You should discuss the different options with your physician “your partner in care” to find out which therapy is right for you.

Hypogonadism is a common condition in the male population, with a higher prevalence in older men, obese men, and men with type 2 diabetes. If you are concerned about your testosterone levels It is important to talk to doctor about ways to manage.

Currently, there are a variety of widely available testosterone formulations, including topical gels and patches, intramuscular injections, subcutaneous pellets, and oral/buccal formulations that provide clinicians and male patients the opportunity to personalize replacement therapy to reestablish testosterone levels and improve testosterone deficiency symptoms ⁸. Method of testosterone replacement therapy treatment depends on the cause of low testosterone, the patient’s preferences, cost, tolerance, and concern about fertility.

• Injections. Self or doctor administered in a muscle every 1–2 weeks; administered at a clinic every 10 weeks for longer-acting. Side effects: uncomfortable, fluctuating symptoms.
• Gels/Solutions. Applied to upper arm, shoulder, inner thigh, armpit. Side effects: may transfer to others via skin contact — must wait to absorb completely into skin.
• Patches. Adhere to skin every day to back, abdomen, upper arm, thigh; rotate locations to lessen skin reaction. Side effects: skin redness and rashes.
• Buccal Tablets. Sticky pill applied to gums twice a day, absorbs quickly into bloodstream through gums. Side effects: gum irritation.
• Pellets. Implanted under skin surgically every 3–6 months for consistent and long-term dosages. Side effects: pellet coming out through skin, site infection/ bleeding (rare), dose decreasing over time and hypogonadism symptoms possibly returning towards the end of dose period.
• Nasal Gel. Applied by pump into each nostril 3x a day. Side effects: nasal irritation or congestion.

Transdermal gels and intramuscular (IM) injections are the top 2 options ⁶.

Oral capsules and tablets of testosterone such as methyltestosterone should generally not be used to treat testosterone deficiency due to hepatic side effects and decreased efficacy when compared with other formulations ⁶. The buccal form should not be chewed or swallowed.

Transdermal formulations include testosterone gels, patches, solutions, and pellets. Testosterone gels are generally recommended due to patient preference, cost, convenience, and insurance coverage. The major advantage of gels is the maintenance of stable serum testosterone concentrations resulting in stable libido, energy, and mood. There are various formulations of testosterone gel. These gels should be applied to the shoulder, upper arms, or abdomen and should not be applied to the scrotum. A study showed the bioavailability of testosterone gel is 30% lower when applied to the abdomen as when compared with arms and shoulders ⁹.

A nasal testosterone gel is now approved in the United States. It should be given 3 times daily. Some patients may find this inconvenient. A testosterone patch should be applied to the back, abdomen, thigh or upper arm and should not be applied to the scrotum. A testosterone solution was discontinued by the FDA in 2017. Subcutaneous testosterone pellets are placed every 3 to 6 months into the subdermal fat of the buttocks, abdominal wall, or thigh but are not routinely recommended due to limited data on the serum testosterone concentrations during treatment.

Intramuscular injections of testosterone include testosterone enanthate and testosterone cypionate. These injections are generally recommended to be given at doses of 50 to 100 mg every week or 100 to 200 mg every 2 weeks ¹⁰. In 2014, the FDA approved an extra-long acting intramuscular injection form of testosterone called testosterone undecanoate, which is dosed at 750 mg followed by a second dose 4 weeks later and subsequent doses every 10 weeks ¹¹. Testosterone undecanoate is not the first-line treatment of choice but generally used when patients do not have access to other forms of treatment.

The most controversial area for TRT is the issue of risk, especially possible stimulation of prostate cancer by testosterone, even though no evidence to support this risk exists. A 2021 study ¹² concluded that compared to TRT-untreated patients, TRT-treated patients may not have increased risks for disease progression in prostate cancer. However, the quality of currently available evidence is extremely poor. TRT may be harmful in men with advanced prostate cancer, in those with untreated prostate cancer undergoing active surveillance, and in those with successfully treated prostate cancer but having high-risk disease ¹². The United States Food and Drug Administration (FDA) stated, in all testosterone package inserts, that TRT is contraindicated in men with known or suspected prostate cancer, but it did not substantiate this contraindication ¹³. The clinical guidelines by Endocrine Society recommend against treating hypogonadism in men with prostate cancer, citing lack of sufficient data to make a general recommendation in men previously treated for prostate cancer (‘recommendation with low quality evidence’) ¹⁴. Meanwhile, the European Association of Urology stated that there is no conclusive evidence that TRT increases the risk of prostate cancer (‘level of evidence=4’), and that men with prostate cancer can receive TRT with careful monitoring for prostate safety (‘level of evidence=3’) ¹⁵. Similarly, the recent treatment guideline by the American Urologic Association stated that patients should be informed that there is inadequate evidence for TRT (‘expert opinion’), but TRT can be considered in men who have undergone radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), without PSA recurrence ¹⁶.

What is testosterone?

Testosterone is the major male sex hormone and is produced by the male testes in men and to a lesser extent by the adrenal glands in both men and women. In men, testosterone is thought to regulate sex drive (libido), bone mass, fat distribution, promotes gains in muscle mass and strength when combined with resistance training, the production of red blood cells and controlling fertility and the development of sperm (spermatogenesis) ¹⁷, ¹⁸. Testosterone also plays an important part in the development of ‘male sex characteristics’ such as a deeper voice and certain patterns of muscle development and hair growth. Testosterone helps bring on the physical changes that turn a boy into a man. This time of life is called puberty. Adolescent boys with too little testosterone may not experience normal masculinization. For example, the genitals may not enlarge, facial and body hair may be scant and the voice may not deepen normally. In women or anyone with ovaries, testosterone impacts overall growth as well as development of muscle and reproductive tissue. Testosterone is produced in the Leydig cells in the testis in men and to a lesser extent by the adrenal glands in both men and women ¹⁹. In males, the normal range for early morning testosterone is between 300 ng/dL to 1000 ng/dL but may vary from laboratory to laboratory ²⁰, ²¹, ²².

Blood levels of testosterone peak in 20 to 30 year-old males and then decline with age with average rate of decline of 1.6% per year ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹. One study found that serum testosterone levels were below the normal range in 20% of men in their 60s and in close to 50% of men in their 80s ²⁶. However, the prevalence of symptomatic low testosterone (hypogonadism) is estimated by some to be much lower in this population, at about 2% ³⁰. Longitudinal studies demonstrated a gradual decline in total serum testosterone levels in men from the age of 40, with 20% and 30% of men meeting age-related low testosterone
criteria in their 60s and 70s ³¹, ³².

Testosterone in the blood can be either bound or free:

• Bound testosterone is attached to proteins such as sex-hormone-binding-globulin (SHBG) and albumin. Most testosterone (approximately 60–70%) is transported in the blood to target tissues bound to sex hormone-binding globulin (SHBG), which in men is also called testosterone-binding globulin. About 30–40% of testosterone is loosely bound to albumin. This majority supply of protein-bound testosterone acts as a surplus of testosterone hormone for the body ³³.
• Free testosterone, the active form, is all the remaining testosterone that is not bound to other substances. The small amounts of free testosterone (approximately 0.5–2%) in the blood act at the level of the tissues, primarily the seminal vesicles, bone, muscle, and prostate gland ³³.

Historically, only free testosterone was thought to be the biologically active component. However, testosterone is weakly bound to serum albumin and dissociates freely in the capillary bed, thereby becoming readily available for tissue uptake. All non-SHBG-bound testosterone is therefore considered bioavailable.

Low testosterone levels in men is defined as total testosterone < 350 ng/dL and free testosterone < 225 pmol/L and are associated with sexual dysfunction such as low sexual desire (low libido), erectile dysfunction (fewer or diminished spontaneous erections, decreased nocturnal penile tumescence), reduced skeletal muscle mass and strength, decreased bone mineral density, sparse beard growth, shrinking testes, increased cardiovascular risk and alterations of the glycometabolic profile ³⁴, ²⁰, ³⁵, ³⁶, ³⁷. The European Urological Association recommends a total testosterone level < 300 ng/dL as the diagnosis of hypogonadism ³⁸, the American Urological Association considers 3.5 ng/mL (12 nmol/L) total testosterone represents a reliable threshold to diagnose age-related hypogonadism ³⁹, and the Endocrine Society recommends the reasonable cut-off of total testosterone in men as 264 ng/dL (9.2 nmol/L) ⁴⁰. This variation total testosterone level diagnostic criteria underscores the lack of uniformity in defining age-related low testosterone across different medical governing bodies. Total testosterone 12 nmol/L (3.5 ng/mL) represents a reliable threshold to diagnose age-related low testosterone
³. Calculated free-testosterone of < 220 pmol/L has been suggested as a possible cut-off to diagnose age-related hypogonadism ³.

Testosterone levels are also potentially influenced by food intake ⁴¹; therefore, serum total testosterone should be measured in fasting conditions in the morning (between 7AM and 11AM). A confirmatory measurement should always be undertaken in the case of a abnormal value, and before starting any testosterone therapy.

In clinical conditions that may interfere with sex hormone-binding globulin (SHBG) levels, evaluation of free testosterone should be considered to better estimate actual androgen levels. Unfortunately, despite free testosterone potential clinical value ⁴², no validated thresholds for free testosterone are available from clinical studies and this represents an area of uncertainty; however, data from the European Male Aging Study indicated that free testosterone levels < 220 pmol/L (6.4 ng/dL) increased the likelihood to correct identify hypogonadism as compared with total testosterone level alone, particularly when total testosterone levels are between 8.0 and 11 nmol per liter ⁴³, ⁴⁴, ³⁰.

The incidence of low testosterone in the United States is reported to be approximately 20% in men older than 60 years of age with 30% in those older than 70 years of age and 50% in those older than 80 years ²⁶, although the prevalence of syndromic low testosterone defined as at least 3 sexual symptoms with a total testosterone level < 320 ng/dL (<11.1 nmol/L) is lower ³⁰.

However, uncertainty exists as to whether nonspecific signs and symptoms associated with age-related low testosterone, such as sexual dysfunction, decreases in energy and muscle mass, mood disturbances, changes in bone mineral density, cardiovascular disease, depression, decreased libido, erectile dysfunction, decreased volume of ejaculate, loss of body and facial hair, weakness, and mortality, are a consequence of age-related low testosterone or whether they are a result of other factors, such as chronic illnesses or concomitant medications ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹. Given the high prevalence of low testosterone and more limited correlation of low testosterone with symptoms in aging men, it is uncertain to what extent does low testosterone represents a physiologic or pathologic event ²⁴, ²⁶. Furthermore, symptoms typically associated with low testosterone are less specific in older men and may be caused by other diseases or medical conditions. For example, erectile dysfunction can be the result of vascular insufficiency, neurologic impairment, psychogenic causes or substance use ⁵⁰. Conditions such as diabetes and atherosclerosis are more common in older men, with up to 40% of men over 50 years of age having evidence of vascular insufficiency as the primary cause of their erectile dysfunction ⁵¹. Low libido similarly can result from psychiatric or medical conditions that are more common in older men ⁵².

The role of testosterone treatment in managing age-related low testosterone is controversial ⁵³. The U.S. Food and Drug Administration (FDA) requires the pharmaceutical industry to label all testosterone medications to clearly state that their products are approved for use only in persons with low testosterone levels due to known causes and the FDA cautions about using testosterone products for low testosterone due to aging; requiring labeling change to inform of possible increased risk of heart attack and stroke with testosterone use ⁵⁴, ⁴⁶.

Testosterone replacement therapy (TRT), a generally accepted method treating for age-related low testosterone, can improve the symptoms of age-related hypogonadism and is most usually administered by injection, oral administration and transdermal administration ⁵⁵. Many studies have reported the benefit of testosterone replacement therapy (TRT) for age-related low testosterone ⁵⁶. However, some studies revealed that symptoms related to age-related hypogonadism may not be correlated with serum total testosterone levels ⁵⁷, ⁵⁸.

The American College of Physicians (ACP) recently issued new guidelines on prescribing supplemental testosterone for men with age-related low testosterone ⁵³:

• The American College of Physicians suggests that clinicians discuss whether to initiate testosterone treatment in men with age-related low testosterone with sexual dysfunction who want to improve sexual function (conditional recommendation; low-certainty evidence). The discussion should include the potential benefits, harms, costs, and patient’s preferences.
• The American College of Physicians suggests that clinicians should reevaluate symptoms within 12 months and periodically thereafter. Clinicians should discontinue testosterone treatment in men with age-related low testosterone with sexual dysfunction in whom there is no improvement in sexual function (conditional recommendation; low-certainty evidence).
• The American College of Physicians suggests that clinicians consider intramuscular rather than transdermal formulations when initiating testosterone treatment to improve sexual function in men with age-related low testosterone, as costs are considerably lower for the intramuscular formulation and clinical effectiveness and harms are similar.
• The evidence shows that men with age-related low testosterone may experience slight improvements in sexual function by 35% and erectile dysfunction by 27% if prescribed supplemental testosterone.
• The evidence does not support prescribing testosterone for men with concerns about energy, vitality, physical function, or cognition.
• The new guidelines point out that treating with supplemental testosterone is not risk free. Potential risks include blood clots, stroke, sleep apnea, acne and possibly enlarged breasts (gynecomastia). Men with these or other conditions may be advised against using supplemental testosterone even for sexual dysfunction.
• If men are treated with supplemental testosterone for sexual dysfunction, the decision to continue to treat should be reevaluated after a year and then periodically after that. Treatment should be stopped if sexual dysfunction doesn’t improve, according to the new guidelines.

Data from meta-analyses have shown that testosterone replacement therapy is ineffective when baseline testosterone levels are > 3.5 ng/mL (>12 nmol/L). Positive outcomes are documented when testosterone levels are < 3.5 ng/mL (<12 nmol/L), being higher in symptomatic patients with more severe forms of hypogonadism (< 8 nmol/L). Hence, 3.5 ng/mL (12 nmol/L) should be considered as a possible threshold for starting testosterone therapy in the presence of hypogonadal symptoms ⁵⁹, ⁶⁰.

You should not receive testosterone therapy if you have:

• Prostate or breast cancer (or suspected)
• Enlarged prostate causing difficulty with urination
• Elevated prostate specific antigen (PSA) levels
• High number of red blood cells
• Untreated sleep apnea (obstructed breathing during sleep)
• Planning to have children
• Heart attack or stroke within the last 6 months
• Blood clots

Possible risks of testosterone treatment include:

• Decreased sperm production
• A high red blood cell count
• Acne
• An increase in prostate size
• Sleep apnea—the occasional stopping of breathing during sleep (rarely)

You should discuss with your doctor how to monitor for prostate cancer and other risks to your prostate. Men with known or suspected prostate or breast cancer should not receive testosterone therapy. You should also talk to your doctor about the risks of testosterone therapy if you have, or are at risk for, heart disease or stroke. In addition, if you are planning fertility, you should not use testosterone therapy.

Figure 1. Testosterone

Figure 2. Hypothalamic–pituitary–gonadal axis

Footnotes: In puberty, the hypothalamic-pituitary-gonadal axis plays a major role in regulating testosterone levels and gonadal function. Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus by GnRH-expressing neurons. The GnRH travels down the hypothalamohypophyseal portal system to the anterior pituitary, which secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are two gonadotropic hormones that travel through the blood and act on receptors in the gonads. The largest amounts of testosterone (>95%) are produced by the testes in men, while the adrenal glands account for most of the remainder. In the testes, testosterone is produced by the Leydig cells ⁶¹. The male testes also contain Sertoli cells, which require testosterone for spermatogenesis (sperm cell development). Luteinizing hormone (LH), in particular, acts on the Leydig cells to increase testosterone production. Testosterone limits its own secretion via negative feedback. High levels of testosterone in the blood feedback to the hypothalamus to suppress the secretion of GnRH and also feedback to the anterior pituitary, making it less responsive to GnRH stimuli ⁶². Throughout the reproductive life of males, the hypothalamus releases GnRH in pulses every 1 to 3 hours. Despite this pulsatile release, however, average plasma levels of FSH and LH remain fairly constant from the start of puberty, where levels spike, to the third decade of life, where levels peak and slowly begin to decline. Prior to puberty, testosterone levels are low, reflecting the low secretion of GnRH and gonadotropins. Changes in neuronal input to the hypothalamus and brain activity during puberty cause a dramatic rise in GnRH secretion.

Figure 3. Testosterone biosynthetic pathways

Footnotes: Biosynthetic pathways for testosterone and dihydrotestosterone (DHT) synthesis. The classic pathway show testosterone synthesized from cholesterol with further metabolism to dihydrotestosterone (DHT). The alternative or “backdoor” pathway shows DHT production without going through testosterone. Note only some of the enzymes are shown for clarity.

[Source ¹⁹ ]

Figure 4. Age-related hypogonadism diagnostic algorithm

Abbreviations: TT = total testosterone; cFT = calculated free testosterone; PRL = prolactin; SHBG = sex hormone-binding globulin; LH = luteinising hormone; MRI = Magnetic resonance imaging.

[Source ³ ]

Normal testosterone levels

A total testosterone test measures both bound and free testosterone in a sample of blood. Total testosterone is the most commonly used test for diagnostic and monitoring purposes and levels are commonly reported in nanograms per deciliter of blood (ng/dL). Less often, a testosterone test may be performed for free testosterone, which is reported in picograms per deciliter of blood (pg/dL). Another less common test is for bioavailable testosterone, which is testosterone that can be used more readily by the body. Bioavailable testosterone includes all testosterone that is not bound to sex-hormone-binding-globulin (SHBG) , including free testosterone and albumin-bound testosterone. Bioavailable testosterone is also commonly reported in nanograms per deciliter of blood (ng/dL).

To measure your testosterone level, your doctor can order a blood test. The blood test should be done in the morning between 7:00 AM and 10:00 AM.

Normal testosterone levels

• Normal total testosterone levels in males: 300 to 1,000 nanograms per deciliter (ng/dL) or 10 to 35 nanomoles per liter (nmol/L). The harmonized normal serum total testosterone range in a healthy nonobese population of European and American men, 19 to 39 years, is 264 to 916 ng/dL ⁶³. Furthermore, in randomized testosterone trials, the men with testosterone levels below the harmonized threshold would be more likely to respond to testosterone therapy than those with testosterone levels above the harmonized threshold.
  • 0-5 months: 75-400 ng/dL
  • 6 months-9 years: <7-20 ng/dL
  • 10-11 years: <7-130 ng/dL
  • 12-13 years: <7-800 ng/dL
  • 14 years: <7-1,200 ng/dL
  • 15-16 years: 100-1,200 ng/dL
  • 17-18 years: 300-1,200 ng/dL
  • Over 19 years: 240-950 ng/dL
• Normal total testosterone levels in females: 15 to 70 ng/dL or 0.5 to 2.4 nmol/L
  • 0-5 months: 20-80 ng/dL
  • 6 months to 9 years: <7-20 ng/dL
  • 10-11 years: <7-44 ng/dL
  • 12-16 years: <7-75 ng/dL
  • 17-18 years: 20-75 ng/dL
  • Over 19 years: 8-60 ng/dL
• Normal free testosterone levels in males:
  • 20-25 years: 5.25-20.7 ng/dL
  • 25-30 years: 5.05-19.8 ng/dL
  • 30-35 years: 4.85-19.0 ng/dL
  • 35-40 years: 4.65-18.1 ng/dL
  • 40-45 years: 4.46-17.1 ng/dL
  • 45-50 years: 4.26-16.4 ng/dL
  • 50-55 years: 4.06-15.6 ng/dL
  • 55-60 years: 3.87-14.7 ng/dL
  • 60-65 years: 3.67-13.9 ng/dL
  • 65-70 years: 3.47-13.0 ng/dL
  • 70-75 years: 3.28-12.2 ng/dL
  • 75-80 years: 3.08-11.3 ng/dL
  • 80-85 years: 2.88-10.5 ng/dL
  • 85-90 years: 2.69-9.61 ng/dL
  • 90-95 years: 2.49-8.76 ng/dL
  • 95-100+ years: 2.29-7.91 ng/dL
• Normal free testosterone levels in females:
  • 20-25 years: 0.06-1.08 ng/dL
  • 25-30 years: 0.06-1.06 ng/dL
  • 30-35 years: 0.06-1.03 ng/dL
  • 35-40 years: 0.06-1.00 ng/dL
  • 40-45 years: 0.06-0.98 ng/dL
  • 45-50 years: 0.06-0.95 ng/dL
  • 50-55 years: 0.06-0.92 ng/dL
  • 55-60 years: 0.06-0.90 ng/dL
  • 60-65 years: 0.06-0.87 ng/dL
  • 65-70 years: 0.06-0.84 ng/dL
  • 70-75 years: 0.06-0.82 ng/dL
  • 75-80 years: 0.06-0.79 ng/dL
  • 80-85 years: 0.06-0.76 ng/dL
  • 85-90 years: 0.06-0.73 ng/dL
  • 90-95 years: 0.06-0.71 ng/dL
  • 95-100+ years: 0.06-0.68 ng/dL

Talk to your doctor about the meaning of your specific test results. Testosterone levels change from hour to hour. Testosterone levels tend to be highest in the morning and lowest at night. Testosterone levels are highest by age 20 to 30 and slowly go down after age 30 to 35. In addition, normal testosterone level ranges may vary slightly among different laboratories. Some labs use different measurements or test different specimens.

If the result is not normal, you should repeat the test to make sure of the result. In healthy men, testosterone levels can change a lot from day to day, so a second test could be normal.

What is the role of testosterone in men’s health?

Testosterone is a hormone produced primarily in the testicles. Testosterone is the most important sex hormone that men have. It is responsible for the typical male characteristics, such as facial, pubic, and body hair as well as muscle. Testosterone hormone also helps maintain sex drive, sperm production, and bone health. The brain and pituitary gland (a small gland at the base of the brain) control the production of testosterone by the testes.

Testosterone helps maintain men’s:

• Bone density
• Fat distribution
• Muscle strength and mass
• Facial and body hair
• Red blood cell production
• Sex drive
• Sperm production

Low testosterone / testosterone deficiency

Testosterone deficiency also known as male hypogonadism, is defined as having one or more symptoms (e.g. decreased libido, decreased erections, decreased energy, decreased physical stamina, decreased lean muscle mass) attributable to low circulating levels of testosterone (morning serum total testosterone less than 300 ng/dL on two separate occasions) ¹⁶, ⁶⁴, ⁶⁵. An estimated 25% of men have low levels of testosterone ⁶⁶. Besides being fundamental for the development and maintenance of male characteristics and male sexual organs, testosterone also has effects on most major organs, such as the brain, muscle, kidney, bone, liver and skin ⁶⁷. Recent studies have also suggested that testosterone deficiency is independently and robustly associated with various obesity-related chronic diseases in men, including type 2 diabetes, hypertension, cardiovascular disease, hyperlipidemia, asthma, chronic obstructive pulmonary disease (COPD) ⁶⁸, ⁶⁹. However, there is uncertainty as to what constitutes optimal physiological levels of total testosterone among men across different age categories, and to the effects that varying total testosterone levels have on disease risk ⁷⁰. This debate is partially fueled by inconsistent findings in the literature and differences across expert clinical recommendations, as well as an incomplete understanding of the underlying mechanisms and temporal sequence of events leading to and stemming from testosterone deficiency. For example, the authors of a well-known systematic review ⁷¹ assert that although testosterone deficiency is robustly associated with obesity, insulin resistance, low high-density lipoprotein (HDL) cholesterol and elevated triglycerides, low-density lipoprotein (LDL) cholesterol, and plasminogen activator type 1, there is insufficient evidence to demonstrate a causal role of endogenous testosterone deficiency on coronary artery disease-the leading cause of preventable death among men in the U.S ⁷².

Incidence of hypogonadism (symptomatic low testosterone) increases with advancing male age such that levels of circulating testosterone decline annually by approximately 1% from the age of 40 years according to the European Male Ageing Study ³⁰. When hypogonadism occurs in an older man, the condition is often called andropause or androgen deficiency of the aging male or late onset hypogonadism (LOH) ⁷³. The most easily recognized clinical signs of late onset hypogonadism (andropause) in older men are a decrease in muscle mass and strength, a decrease in bone mass and osteoporosis, decreased libido, erectile dysfunction, anemia, increase in central body fat, and impaired memory, mood, concentration, and sleep ⁷⁴, as well as increased mortality ⁷⁵. Sexual symptoms and fatigue are the earliest and most common presentations ⁷⁶. Other symptoms include depression, sleep alterations, poor concentration, and metabolic disorders are seen at borderline testosterone levels ⁷⁷, ⁷⁸. However, symptoms such as a decrease in libido and sexual desire, forgetfulness, loss of memory, anemia, difficulty in concentration, insomnia, and a decreased sense of well-being are more difficult to measure and differentiate from hormone-independent aging ⁷⁹. Androgen deficiency of the aging male may result in significant detriment to quality of life and adversely affect the function of multiple organ systems ⁸⁰.

The pathophysiology of male hypogonadism can be characterized into two types ⁸¹:

1. Primary hypogonadism also known as primary testicular failure or hypergonadotropic hypogonadism. Primary hypogonadism is a testosterone deficiency due to a testicular abnormality impairing testosterone production; for example, Klinefelter syndrome, testicular tumors, infection, trauma, impaired Leydig cell function, or those caused by certain medications ⁸².
2. Secondary hypogonadism also known as hypogonadotropic hypogonadism. Secondary hypogonadism is a testosterone deficiency due to a problem in the hypothalamus or the pituitary gland, parts of the brain that signal the testicles to produce testosterone (i.e., luteinizing hormone (LH) and follicle-stimulating hormone (FSH)); for example, hypothalamic or pituitary lesions, GnRH deficiency, or hyperprolactinemia ⁸². Another important cause of hypogonadism is late-onset hypogonadism, an age-related (i.e., >40 years) decline in testosterone accompanied by clinical symptoms that is often associated with obesity, diabetes, and other chronic health conditions ⁸³.

Risk factors for hypogonadism include:

• HIV/AIDS
• Previous chemotherapy or radiation therapy
• Aging
• Obesity
• Malnutrition

Late-onset hypogonadism (andropause) has the combined features of both primary and secondary hypogonadism ⁸⁴. The diagnosis of andropause (late-onset hypogonadism) requires the presence of characteristic signs and symptoms, in combination with decreased serum total testosterone. Based on the recent guidelines by the International Society for the Study of Aging Male (ISSAM), the European Association of Urology (EAU), the European Society of Endocrinology (ESE), the European Academy of Andrology (EAA), and the American Association of Urology (AUA), a total testosterone of 250–350 ng/dL is the proper threshold value to define low testosterone. The optimal indication for TRT in late-onset hypogonadism (andropause) is the presence of signs and symptoms of hypogonadism, and low testosterone without contraindications for TRT ⁸⁵.

What causes low testosterone?

Testosterone deficiency also known as male hypogonadism, is defined as having one or more symptoms (e.g. decreased libido, decreased erections, decreased energy, decreased physical stamina, decreased lean muscle mass) attributable to low circulating levels of testosterone (morning serum total testosterone less than 300 ng/dL on two separate occasions) ¹⁶, ⁶⁴, ⁶⁵.

There are two basic types of hypogonadism:

1. Primary. This type of hypogonadism — also known as primary testicular failure — originates from a problem in the testicles.
2. Secondary. This type of hypogonadism indicates a problem in the hypothalamus or the pituitary gland — parts of the brain that signal the testicles to produce testosterone. The hypothalamus produces gonadotropin-releasing hormone, which signals the pituitary gland to make follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Luteinizing hormone then signals the testes to produce testosterone.

Either type of hypogonadism can be caused by an inherited (congenital) trait or something that happens later in life (acquired), such as an injury or an infection. At times, primary and secondary hypogonadism occur together.

Primary hypogonadism

Common causes of primary hypogonadism include:

• Klinefelter syndrome also known as 47,XXY or XXY male. Klinefelter syndrome results from a congenital abnormality of the sex chromosomes, X and Y. A male normally has one X and one Y chromosome. In Klinefelter syndrome, two or more X chromosomes are present in addition to one Y chromosome. The Y chromosome contains the genetic material that determines the sex of a child and related development. The extra X chromosome typically affects physical, neurodevelopmental, behavioral, and neurocognitive functioning. Common physical features may include tall stature, reduced muscle tone, abnormal development of the testicles (hypogonadism), which in turn results in underproduction of testosterone with delayed pubertal development and lack of secondary male sex characteristics such as decreased facial and body hair. Increased breast growth (gynecomastia) may occur later in puberty without appropriate biological care.
• Undescended testicles (cryptorchidism). Before birth, the testicles develop inside the abdomen and normally move down into their permanent place in the scrotum. Sometimes one or both of the testicles aren’t descended at birth. This condition often corrects itself within the first few years of life without treatment. If not corrected in early childhood, it can lead to malfunction of the testicles and reduced production of testosterone.
• Mumps orchitis. A mumps infection involving the testicles that occurs during adolescence or adulthood can damage the testicles, affecting the function of the testicles and testosterone production.
• Hemochromatosis. Too much iron in the blood can cause testicular failure or pituitary gland dysfunction, affecting testosterone production.
• Injury to the testicles. Because they’re outside the abdomen, the testicles are prone to injury. Damage to both testicles can cause hypogonadism. Damage to one testicle might not impair total testosterone production.
• Cancer treatment. Chemotherapy or radiation therapy for the treatment of cancer can interfere with testosterone and sperm production. The effects of both treatments often are temporary, but permanent infertility may occur. Although many men regain their fertility within a few months after treatment, preserving sperm before starting cancer therapy is an option for men.

Secondary hypogonadism

In secondary hypogonadism, the testicles are normal but don’t function properly due to a problem with the pituitary or hypothalamus. A number of conditions can cause secondary hypogonadism, including:

• Kallmann’s syndrome. This is an abnormal development of the area of the brain that controls the secretion of pituitary hormones (hypothalamus). This abnormality can also affect the ability to smell (anosmia) and cause red-green color blindness.
• Pituitary disorders. An abnormality in the pituitary gland can impair the release of hormones from the pituitary gland to the testicles, affecting normal testosterone production. A pituitary tumor or other type of brain tumor located near the pituitary gland may cause testosterone or other hormone deficiencies. Also, treatment for a brain tumor, such as surgery or radiation therapy, can affect the pituitary gland and cause hypogonadism.
• Inflammatory disease. Certain inflammatory diseases, such as sarcoidosis, histiocytosis and tuberculosis, involve the hypothalamus and pituitary gland and can affect testosterone production.
• HIV/AIDS. HIV/AIDS can cause low levels of testosterone by affecting the hypothalamus, the pituitary and the testes.
• Medications. The use of certain drugs, such as opiate pain medications and some hormones, can affect testosterone production.
• Obesity. Being significantly overweight at any age might be linked to hypogonadism.
• Aging. As men age, there’s a slow, progressive decrease in testosterone production. The rate varies greatly.

Age related low testosterone causes

As men age, there’s a slow, progressive decrease in testosterone or “T” production. Blood levels of testosterone peak in 20 to 30 year-old males and then decline with age with average rate of decline of 1.6% per year ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹. One study found that serum testosterone levels were below the normal range in 20% of men in their 60s and in close to 50% of men in their 80s ²⁶. However, the prevalence of symptomatic low testosterone (hypogonadism) is estimated by some to be much lower in this population, at about 2% ³⁰. Longitudinal studies demonstrated a gradual decline in total serum testosterone levels in men from the age of 40, with 20% and 30% of men meeting age-related low testosterone criteria in their 60s and 70s ³¹, ³².

Risk factors for hypogonadism include:

• HIV/AIDS. HIV/AIDS can cause low levels of testosterone by affecting the hypothalamus, the pituitary and the testes.
• Medications. The use of certain drugs, such as opiate pain medications and some hormones, can affect testosterone production.
• Previous chemotherapy or radiation therapy. Chemotherapy or radiation therapy for the treatment of cancer can interfere with testosterone and sperm production. The effects of both treatments often are temporary, but permanent infertility may occur. Although many men regain their fertility within a few months after treatment, preserving sperm before starting cancer therapy is an option for men.
• Obesity. Being significantly overweight at any age might be linked to hypogonadism.
• Undescended testicles (cryptorchidism). Before birth, the testicles develop inside the abdomen and normally move down into their permanent place in the scrotum. Sometimes one or both of the testicles aren’t descended at birth. This condition often corrects itself within the first few years of life without treatment. If not corrected in early childhood, it can lead to malfunction of the testicles and reduced production of testosterone.
• Mumps orchitis. A mumps infection involving the testicles that occurs during adolescence or adulthood can damage the testicles, affecting the function of the testicles and testosterone production.
• Hemochromatosis. Too much iron in the blood can cause testicular failure or pituitary gland dysfunction, affecting testosterone production.
  Injury to the testicles. Because they’re outside the abdomen, the testicles are prone to injury. Damage to both testicles can cause hypogonadism. Damage to one testicle might not impair total testosterone production.
• Malnutrition or nutritional deficiencies.
  
• Pituitary disorders. An abnormality in the pituitary gland can impair the release of hormones from the pituitary gland to the testicles, affecting normal testosterone production. A pituitary tumor or other type of brain tumor located near the pituitary gland may cause testosterone or other hormone deficiencies. Also, treatment for a brain tumor, such as surgery or radiation therapy, can affect the pituitary gland and cause hypogonadism.
• Inflammatory disease. Certain inflammatory diseases, such as sarcoidosis, histiocytosis and tuberculosis, involve the hypothalamus and pituitary gland and can affect testosterone production.
• Kallmann’s syndrome. This is an abnormal development of the area of the brain that controls the secretion of pituitary hormones (hypothalamus). This abnormality can also affect the ability to smell (anosmia) and cause red-green color blindness.
• Klinefelter syndrome. Klinefelter syndrome results from a congenital abnormality of the sex chromosomes, X and Y. A male normally has one X and one Y chromosome. In Klinefelter syndrome, two or more X chromosomes are present in addition to one Y chromosome. The Y chromosome contains the genetic material that determines the sex of a child and related development. The extra X chromosome that occurs in Klinefelter syndrome causes abnormal development of the testicles, which in turn results in underproduction of testosterone.

Hypogonadism can be inherited. If any of these risk factors are in your family health history, tell your doctor.

What happens to testosterone levels with age?

Testosterone levels generally peak during adolescence and early adulthood. As you get older, your testosterone level gradually declines — typically about 1 percent a year after age 30 or 40. It is important to determine in older men if a low testosterone level is simply due to the decline of normal aging or if it is due to a disease (hypogonadism).

Hypogonadism is a disease in which the body is unable to produce normal amounts of testosterone due to a problem with the testicles or with the pituitary gland that controls the testicles. Testosterone replacement therapy can improve the signs and symptoms of low testosterone in these men. Doctors may prescribe testosterone as injections, pellets, patches or gels.

In the short term, low testosterone also called hypogonadism can cause:

• A drop in sex drive
• Poor erections
• Low sperm count
• Enlarged breasts

Over time, low testosterone may cause a man to lose body hair, muscle bulk, and strength and to gain body fat. Chronic (long-term) low testosterone may also cause weak bones (osteoporosis), mood changes, less energy, and smaller testes. Signs and symptoms (what you see and feel) vary from person to person.

Does a naturally declining testosterone level cause the signs and symptoms of aging?

Not necessarily. Men can experience many signs and symptoms as they age. Some may occur as a result of lower testosterone levels and can include:

• Changes in sexual function. This may include reduced sexual desire, fewer spontaneous erections — such as during sleep — and infertility.
• Changes in sleep patterns. Sometimes low testosterone causes insomnia or other sleep disturbances.
• Physical changes. Various physical changes are possible, including increased body fat, reduced muscle bulk and strength, and decreased bone density.
• Swollen or tender breasts (gynecomastia) and body hair loss are possible. You may have less energy than you used to.
• Emotional changes. Low testosterone may contribute to a decrease in motivation or self-confidence. You may feel sad or depressed, or have trouble concentrating or remembering things.

Some of these signs and symptoms can be caused by various underlying factors, including medication side effects, obstructive sleep apnea, thyroid problems, diabetes and depression. It’s also possible that these conditions may be the cause of low testosterone levels, and treatment of these problems may cause testosterone levels to rise. A blood test is the only way to diagnose a low testosterone level.

How is low testosterone diagnosed?

During a physical exam, your doctor will examine your body hair, breasts, penis, and the size and consistency of the testes and scrotum. Your doctor may check for loss of side (peripheral) vision, which could indicate a pituitary tumor, a rare cause of low testosterone.

Your doctor will also use blood tests to see if your total testosterone level is low. The normal range is generally 300 to 1,000 ng/dL, but this depends on the lab that conducts the test. To get a diagnosis of low testosterone, you may need more than one early morning (7–10 AM) blood test and, sometimes, tests of pituitary gland hormones.

If you have symptoms of low testosterone, your doctor may suggest that you talk with an endocrinologist. This expert in hormones can help find the cause. Be open with your doctor about your medical history, all prescription and nonprescription drugs you are now taking, sexual problems, and any major changes in your life.

Hypogonadism is diagnosed when the morning serum testosterone level is less than 300 ng/dL ⁶. However, clinical judgment is required when making the diagnosis of hypogonadism in a patient who has testosterone levels in the normal range but has persistent symptoms of testosterone deficiency ⁸⁶. Of note, total testosterone less than 405.9 ng/dL is below the fifth percentile ⁸⁷. In older men, one should aim for testosterone levels between 500 and 800 ng/dL while young adults should aim for testosterone levels between 600 and 900 ng/dL ⁶.

Initial laboratory testing should include 2 early mornings (8 AM to 10 AM) measurements of serum testosterone. If both measurements are low, then certain studies should be ordered to rule out secondary hypogonadism. Further testing includes FSH (follicle-stimulating hormone), LH (luteinizing hormone), prolactin, TSH (thyroid-stimulating hormone), complete blood count (CBC), and comprehensive metabolic panel. In cases of low normal testosterone with clinical symptoms, further testing to assess free or bioavailable testosterone should be done. These tests include sex hormone binding globulin (SHBG) and albumin to calculate the bioavailable testosterone which can be affected by obesity, type 2 diabetes, hypothyroidism, and liver disease.

Furthermore, semen analysis, pituitary MRI, testicular ultrasound and biopsy, and genetic studies can be ordered, if there is clinical suspicion of a secondary cause.

Medical History

Specific symptoms associated with hypogonadism, including age-related low testosterone, are shown in Table 1. These symptoms are non-specific and need to be recorded and taken in context with the clinical and biochemical state. Several self-reported questionnaires or structural interviews have been developed for screening of hypogonadism. Although these case-history tools have demonstrated clinical utility in supporting the biochemical diagnosis of hypogonadism, or in the assessment of testosterone therapy outcomes, their specificity remains poor and they should not be used for a systematic screening of hypogonadal men ⁸⁸. Headache and/or visual disturbance may indicate a pituitary-related disorder. History of surgical intervention for undescended testicle (cryptorchidism) or hypospadias (a condition in which the urethral opening of the penis is on the underside rather than at the tip) must be taken into account as possible signs of congenital defects. Chronic and systemic diseases or medical conditions must be comprehensively investigated in every patient. Use of drugs that potentially interfere with the hypothalamic-pituitary-gonadal axis (HPG axis) should be excluded. Acute diseases are associated with development of functional hypogonadism and determination of serum total testosterone levels should be avoided in these conditions; however, the role of testosterone in the case of acute illness remains to be clarified ⁸⁹, ⁹⁰, ⁹¹. Fertility issues should be always discussed.

Table 1. Age-related hypogonadism symptoms

	Sexual symptoms	Physical symptoms	Psychological symptoms
More specific	Reduced libido Erectile dysfunction Decreased spontaneous/morning erections	Decreased vigorous activity Difficulty walking > 1 km Decreased bending	Low mood/mood deflection Decreased motivation Fatigue
Less specific	Reduced frequency of sexual intercourse Reduced frequency of masturbation Delayed ejaculation	Hot flushes Decreased energy Decreased physical strength/function/ activity	Concentration difficulties Sleep disturbances

[Source ³ ]

Physical Examination

Since obesity is frequently associated with hypogonadism (mostly functional), the determination of body mass index (BMI) and the measurement of waist circumference are strongly recommended in all individuals. Testicular and penile size, as well as the presence of sexual secondary characteristics can provide useful information regarding overall androgen status. In addition, upper segment/lower segment ratio (n.v. > 0.92) and arm-span to height ratio (n.v. < 1.0) can be useful to identify a eunuchoid body shape, especially in subjects with pre-pubertal hypogonadism or delayed puberty. Finally, digital rectal examination (DRE) should be performed in all subjects to exclude prostate abnormalities before testosterone therapy (any type) or to support suspicion of hypogonadism (in case of reduced volume) ⁹².

Laboratory tests

Testosterone levels are produced in a circadian variation being highest in the morning and lowest at night, which may persist in ageing men ⁹³, ⁹⁴. Testosterone levels are also potentially influenced by food intake ⁴¹. Therefore, serum total testosterone should be measured in fasting conditions in the morning (between 7 a.m. and 11 a.m.). Testosterone levels can also be temporarily lower due to too much exercise, poor nutrition, severe illness, and with certain medications. A confirmatory measurement should always be undertaken in the case of a abnormal value, and before starting any testosterone therapy.

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) represents the most accurate method for sex steroid evaluation; however, standardised automated platform immuno-assays for total testosterone assessment demonstrate a good correlation with Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) ⁹⁵. Available immuno-assays are not able to provide an accurate estimation of free testosterone; therefore, direct free testosterone evaluation with these methods is not recommended and should be avoided ⁹⁶. Equilibrium dialysis is the most accurate method for total testosterone measurement and free testosterone calculation ⁹⁷. Alternatively, free testosterone can be derived from specific mathematical calculations using total testosterone as derived by common immunoassays and taking into account serum sex hormone binding globulin (SHBG) and albumin levels ⁹⁸.

Low testosterone levels in men is defined as total testosterone < 350 ng/dL and free testosterone < 225 pmol/L and are associated with sexual dysfunction such as low sexual desire (low libido), erectile dysfunction (fewer or diminished spontaneous erections, decreased nocturnal penile tumescence), reduced skeletal muscle mass and strength, decreased bone mineral density, sparse beard growth, shrinking testes, increased cardiovascular risk and alterations of the glycometabolic profile ³⁴, ²⁰, ³⁵, ³⁶, ³⁷. The European Urological Association recommends a total testosterone level < 300 ng/dL as the diagnosis of hypogonadism ³⁸, the American Urological Association considers 3.5 ng/mL (12 nmol/L) total testosterone represents a reliable threshold to diagnose age-related hypogonadism ³⁹, and the Endocrine Society recommends the reasonable cut-off of total testosterone in men as 264 ng/dL (9.2 nmol/L) ⁴⁰. This variation total testosterone level diagnostic criteria underscores the lack of uniformity in defining age-related low testosterone across different medical governing bodies.

Data from meta-analyses have shown that testosterone therapy is ineffective when baseline levels are > 3.5 ng/mL (>12 nmol/L). Positive outcomes are documented when testosterone levels are <3.5 ng/mL (<12 nmol/L), being higher in symptomatic patients with more severe forms of hypogonadism (< 8 nmol/L). Hence, 3.5 ng/mL (12 nmol/L) should be considered as a possible threshold for starting testosterone therapy in the presence of hypogonadal symptoms ⁵⁹, ⁶⁰.

In clinical conditions that may interfere with sex-hormone-binding-globulin (SHBG) levels, evaluation of free testosterone should be considered to better estimate actual androgen levels. Unfortunately, despite free testosterone potential clinical value ⁴², no validated thresholds for free testosterone are available from clinical studies and this represents an area of uncertainty; however, data from the European Male Aging Study indicated that free testosterone levels < 220 pmol/L (6.4 ng/dL) increased the likelihood to correct identify hypogonadism as compared with total testosterone level alone, particularly when total testosterone levels are between 8.0 and 11 nmol per liter ⁴³, ⁴⁴, ³⁰.

The determination of luteinizing hormone (LH) must be performed along with prolactin (PRL) when pathological total testosterone levels are detected, in order to correctly define the underlying conditions and exclude possible organic causes. Follicle-stimulating hormone (FSH) determination can further support the diagnosis of primary or secondary hypogonadism ², ⁹⁹. Due to prolactin (PRL) negative influence on libido, prolactin (PRL) can also be considered as first-line screening in patients with reduced sexual desire. In addition, contrast-enhanced pituitary magnetic resonance imaging (MRI) scanning, as well as other pituitary hormone evaluations, is required in the presence of specific symptoms such as visual disturbances, headache and when hyperprolactinemia is confirmed ¹⁰⁰, ¹⁰¹. Limited evidence suggests also performing pituitary MRI in the case of severe hypogonadism (< 6 nmol/L, 1.75 ng/mL) with inadequate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels ¹⁰⁰, ¹⁰¹, ¹⁰².

How is low testosterone treated?

Testosterone replacement therapy (TRT), a generally accepted method treating for age-related low testosterone, can improve the symptoms of age-related low testosterone and is most usually administered by injection, oral administration and transdermal administration ⁵⁵. Many studies have reported the benefit of testosterone replacement therapy (TRT) for age-related hypogonadism ⁵⁶. However, some studies revealed that symptoms related to age-related hypogonadism may not be correlated with serum total testosterone levels ⁵⁷, ⁵⁸.

The American College of Physicians (ACP) recently issued new guidelines on prescribing supplemental testosterone for men with age-related low testosterone ⁵³:

• The American College of Physicians suggests that clinicians discuss whether to initiate testosterone treatment in men with age-related low testosterone with sexual dysfunction who want to improve sexual function (conditional recommendation; low-certainty evidence). The discussion should include the potential benefits, harms, costs, and patient’s preferences.
• The American College of Physicians suggests that clinicians should reevaluate symptoms within 12 months and periodically thereafter. Clinicians should discontinue testosterone treatment in men with age-related low testosterone with sexual dysfunction in whom there is no improvement in sexual function (conditional recommendation; low-certainty evidence).
• The American College of Physicians suggests that clinicians consider intramuscular rather than transdermal formulations when initiating testosterone treatment to improve sexual function in men with age-related low testosterone, as costs are considerably lower for the intramuscular formulation and clinical effectiveness and harms are similar.
• The evidence shows that men with age-related low testosterone may experience slight improvements in sexual function by 35% and erectile dysfunction by 27% if prescribed supplemental testosterone.
• The evidence does not support prescribing testosterone for men with concerns about energy, vitality, physical function, or cognition.
• The new guidelines point out that treating with supplemental testosterone is not risk free. Potential risks include blood clots, stroke, sleep apnea, acne and possibly enlarged breasts (gynecomastia). Men with these or other conditions may be advised against using supplemental testosterone even for sexual dysfunction.
• If men are treated with supplemental testosterone for sexual dysfunction, the decision to continue to treat should be reevaluated after a year and then periodically after that. Treatment should be stopped if sexual dysfunction doesn’t improve, according to the new guidelines.

Data from meta-analyses have shown that testosterone replacement therapy is ineffective when baseline testosterone levels are > 3.5 ng/mL (>12 nmol/L). Positive outcomes are documented when testosterone levels are < 3.5 ng/mL (<12 nmol/L), being higher in symptomatic patients with more severe forms of hypogonadism (< 8 nmol/L). Therefore, patients with symptomatic hypogonadism without specific contraindications where testosterone levels are less than 3.5 ng/mL (<12 nmol/L) should be considered for starting testosterone therapy ⁵⁹, ⁶⁰.

There are potential risks with long-term use of testosterone. You should discuss with your physician how to monitor for prostate cancer and other risks to your prostate. Men with known or suspected prostate cancer, or with breast cancer, should not receive testosterone treatment.

Other possible risks of testosterone treatment include:

Testosterone therapy carries various risks, including:

• Increased production of red blood cells
• Acne
• Enlarged breasts
• Sleep disturbances
• Prostate enlargement
• Limited sperm production
• Sleep apnea—the occasional stopping of breathing during sleep (rarely)
• Fluid buildup (edema) in ankles, feet and legs (rarely)

Can testosterone replacement therapy promote youth and vitality?

Testosterone replacement therapy can help reverse the effects of hypogonadism, but it’s unclear whether testosterone replacement therapy would have any benefit for older men who are otherwise healthy.

Although some men believe that taking testosterone medications may help them feel younger and more vigorous as they age, few rigorous studies have examined testosterone therapy in men who have healthy testosterone levels. And some small studies have revealed mixed results. For example, in one study healthy men who took testosterone medications increased muscle mass but didn’t gain strength.

Should I talk to my doctor about testosterone replacement therapy?

If you wonder whether testosterone therapy might be right for you, talk with your doctor about the risks and benefits. Your doctor will likely measure your testosterone levels at least twice before discussing whether testosterone replacement therapy is an option for you.

A medical condition that leads to an unusual decline in testosterone may be a reason to take supplemental testosterone. However, treating normal aging with testosterone therapy is not currently advisable.

Your doctor will also likely suggest natural ways to boost testosterone, such as losing weight and increasing muscle mass through resistance exercise.

Benefits of testosterone replacement therapy for men

• Low testosterone comes with age — testosterone levels naturally decrease by 1% each year after age 30, though don’t severely deplete, even in advanced age
• Testosterone production may be disrupted by disorders of the testicles, pituitary gland, or brain
• Testosterone levels change from hour to hour — highest in the morning; lowest at night
• Testosterone levels can temporarily lower due to too much exercise, poor nutrition, severe illness, and with certain medications
• Normal testosterone levels should be between 300–1,000 ng/dL (nanograms per deciliter), depending on age and lab used
• Testosterone must be measured more than once for accurate assessment

Testosterone therapy is only recommended for hypogonadism patients. Boosting testosterone is NOT approved by the US Food and Drug Administration (FDA) to help improve your strength, athletic performance, physical appearance, or to treat or prevent problems associated with aging. Using testosterone for these purposes may be harmful to your health.

Male hypogonadism is a combination of low testosterone levels and the presence of any of these symptoms:

• Drop in sex drive (libido)
• Erectile dysfunction (ED — inability to get or keep an erection) and loss of spontaneous erections
• Lowered sperm count and infertility (inability to have children)
• Breast enlargement or tenderness
• Reduced energy
• Reduced muscle mass
• Shrinkage of testes
• Increased irritability, inability to concentrate, and depressed mood
• Hot flashes (when testosterone levels are very low)

You should NOT receive testosterone therapy if you have:

• Prostate or breast cancer (or suspected)
• Enlarged prostate causing difficulty with urination
• Elevated prostate specific antigen (PSA) levels
• High number of red blood cells
• Untreated sleep apnea (obstructed breathing during sleep)
• Planning to have children
• Heart attack or stroke within the last 6 months
• Blood clots

Testosterone replacement therapy types

Several testosterone formulations are available. Direct comparisons among different testosterone products are still lacking. Patients who are considering testosterone therapy should be adequately informed about the possible risks and benefits of all available testosterone preparations. The final choice should be based on the clinical situation, testosterone formulation availability, and patient needs and expectations ¹⁰³, ¹⁰⁴.

One Food and Drug Administration-approved oral testosterone replacement preparation, testosterone undecanoate (Jatenzo), is absorbed by the lymph system. It might avoid the liver problems seen with other oral forms of testosterone.

Other preparations you might choose, depending on convenience, cost and your insurance coverage, include:

• Testosterone Gel. There are several gels and solutions available, with different ways of applying them. Depending on the brand, you rub the testosterone into your skin on your upper arm or shoulder (AndroGel, Testim, Vogelxo) or apply it to the front and inner thigh (Fortesta). Your body absorbs testosterone through your skin. Don’t shower or bathe for several hours after a gel application, to be sure it gets absorbed. Side effects include skin irritation and the possibility of transferring the medication to another person. Avoid skin-to-skin contact until the gel is completely dry, or cover the area after an application.
• Testosterone Injection. Testosterone cypionate (Depo-Testosterone) and testosterone enanthate are given in a muscle or under the skin. Your symptoms might waver between doses depending on the frequency of injections. You or a family member can learn to give testosterone injections at home. If you’re uncomfortable giving yourself injections, member of your care team can give the injections.
  • Testosterone undecanoate (Aveed) is given by deep intramuscular injection, typically every 10 weeks. It must be given at your provider’s office and can have serious side effects.
• Testosterone Patch. A patch containing testosterone (Androderm) is applied each night to your thighs or torso. A possible side effect is severe skin reaction.
• Testosterone Pellets (Testopel): Testosterone-containing pellets are surgically implanted under the skin every three to six months for consistent and long-term dosages. Side effects: pellet coming out through skin, site infection/ bleeding (rare), dose decreasing over time and hypogonadism symptoms possibly returning towards the end of dose period.
• Testosterone Gum and Cheek (buccal cavity). A small putty-like substance, gum-and-cheek testosterone replacement delivers testosterone through the natural depression above your top teeth where your gum meets your upper lip (buccal cavity). This product, taken three times a day, sticks to your gumline and allows testosterone to be absorbed into your bloodstream. It can cause gum irritation.
• Testosterone Nasal. This testosterone gel (Natesto) can be pumped into the nostrils. This option reduces the risk that medication will be transferred to another person through skin contact. Nasal-delivered testosterone must be applied twice in each nostril, three times daily, which might be more inconvenient than other delivery methods.

Table 2. Testosterone replacement therapy formulations

Names	Strengths	Limitations	Comparative Efficacy	References
Testosterone undecanoate	Bypasses first-pass liver metabolism due to aliphatic side chain and is absorbed directly by the lymphatic system and then by blood	Requires large and frequent dosing to mimic physiologic testosterone levels Serum concentration difficult to predict due to high intra- and inter-individual variability Risk of increased blood pressure and cardiac events	A small but significant increase in systolic blood pressure versus topical testosterone (gel or patch), A greater number of gastrointestinal-associated side effects compared to topical testosterone 105	Nieschlag 2015 106, Swerdloff et al. 2020 107
Striant (testosterone buccal)	Requires only 2x/day dosing to result in stable serum testosterone concentrations and mimics physiologic circadian rhythm release Medication effects can easily be reversed due to easy access of tablets in the oral cavity	Side effects of local irritation, inflammation, or gingivitis in some patients	Superior to testosterone patch (Androderm) 108 Equal to testosterone gel (AndroGel) 109	Tsametis & Isidori 2018 110, Dinsmore & Wyllie 2012 111
Long acting testosterone: Testosterone enanthate, Testosterone cypionate Extra-long acting testosterone: Testosterone undecanoate	More lipophilic than other formulations allowing for extended storage, gradual release, and prolonged presence of testosterone in the blood Requires fewer administrations 2-4x/month (long acting) or 1-2x/2 months (extra-long acting) Easy access Cost effective	Pain associated with deep intramuscular administration Fluctuations in energy, mood, and libido in many patients Risk of pulmonary oil microembolism and anaphylaxis with extra-long acting formulation	Equal to testosterone gel (AndroGel) 112	Nieschlag 2015 106, Tsametis & Isidori 2018 110, Middleton et al. 2015 113
Testosterone Gel: AndroGel®, Testim®, and Fortesta® Testosterone Solution: Axiron® Testosterone Patch: Androderm®	Mimics physiologic diurnal release Short duration of action, allowing for quick discontinuation User friendly	Requires daily administration High cost Side effects of skin irritation and potential contact transfer to another person Less effective in obese individuals	AndroGel equal to Androderm 114 AndroGel equal to Depo Testosterone 112 AndroGel equal to Delatestryl (Testosterone Enanthate) 112 AndroGel Equal to Striant (testosterone buccal) 109 Testim superior to Androderm 115 Testim superior to AndroGel 116	Tsametis & Isidori 2018 110
Testosterone implant: Testopel®	Only requires implantation of pellets every 4-6 months No risk of contact transference	Necessity for surgical procedure to implant sub dermally Risk of pellet extrusion, infection, and fibrosis		Tsametis & Isidori 2018 110
Testosterone nasal: Natesto®	Decreased risk of transference due to inconspicuous site of application Non-invasive and user-friendly Increases testosterone, while maintaining FSH, LH, and semen parameters	Side effects of runny nose (rhinorrhea), nose bleed (epistaxis), nasopharyngitis, sinusitis, and nasal scabbing	Maintenance of spermatogenesis in >95% of men, in contrast to injections or gels. Short duration of action, frequency of administration and clinical pharmacokinetic profile compared to long-acting testosterone injections, gels and pellets 117.	Tsametis & Isidori 2018 110, Gronski et al. 2019 118, Rogol et al. 2018 119

Testosterone Oral formulations

An oral formulation has been available in oleic acid since the 1970s, and has been recently reformulated in a mixture of castor oil and propylene glycol laureate (testosterone undecanoate [TU] caps), to allow the drug to be maintained at room temperature without degradation ¹⁰³, ¹⁰⁴. The main limitation is related to poor bioavailability, which is strongly dependent on dietary fat content ¹⁰³, ¹⁰⁴. The US Food and Drug Administration (FDA) approved a new formulation of oral testosterone undecanoate in a liquid-filled soft gel capsule, which improved oral availability ¹²⁰. Available evidence showed that testosterone undecanoate capsule formulations can reach steady 24-hour average serum testosterone levels in more than 80% of hypogonadal men, thus resulting in a significant improvement of all sexual function domains at all time points when compared to baseline along with an excellent safety profile ¹²⁰. More recently, the FDA has approved a new oral formulation which contains as carriers Vitamin E, phytosterol esters, polyoxyl 40 hydrogenated castor oil and propylene glycol monolaurate ¹²⁰. For all new oral testosterone undecanoate formulations a mild increase in arterial blood pressure has been reported. Hence, the FDA has required a black box warning that these drugs can induce a blood pressure increase ¹²⁰.

Mesterolone is a 5α-dihydrotestosterone (DHT) derivate available for oral administration. Along with DHT, mesterolone cannot be converted to estrogens and can only be used for a limited period and for specific indications, such as the presence of painful gynecomastia. However, the lack of a full spectrum of testosterone bioactivity strongly limits its long-term use ¹⁰³.

Testosterone Injectable formulations

Injectable testosterone preparations can be classified according to their half-lives. Testosterone propionate is a short-term ester formulation requiring multiple fractionated doses (usually 50-100 mg, every two to three days), thus representing a major limitation for its use ¹⁰³, ¹⁰⁴. Cypionate and enanthate-testosterone esters are short-term formulations, requiring administration every two to four weeks. A formulation containing mixed testosterone esters (testosterone undecanoate, isocaproate, phenyl propionate, propionate) which has the benefit of a steady release of testosterone into the circulation, is available in some countries. The use of these older formulations is associated with wide fluctuations in plasma testosterone concentrations and is often reported as unpleasant by patients potentially resulting in adverse effects, such as polycythaemia ¹⁰³, ¹⁰⁴, ¹²¹. A longer-lasting testosterone undecanoate injectable formulation is widely available ¹⁰³, ¹⁰⁴, with a good safety/benefit profile allowing the maintenance of normal stable testosterone levels at a dose of 1,000 mg initially every twelve weeks, following a six-week loading dose, but can be adjusted to a frequency of ten to fourteen weeks dependent on the trough (pre-injection level) after three to five injections to maintain levels in the therapeutic range (usually > 12 and < 18 nmol/L) ¹⁰³, ¹⁰⁴, ¹²².

Testosterone Transdermal preparations

Among the available transdermal formulations, testosterone gels represent the most frequently used preparations. The testosterone gel is quickly absorbed by the stratum corneum, creating a reservoir within the subcutaneous tissues from where testosterone is continuously delivered for 24 hours, after a single daily application. These formulations have been shown to normalise serum testosterone levels with an excellent safety profile ¹⁰³, ¹⁰⁴, ¹²². The introduction of specific devices and skin enhancers has resulted in better skin penetration of the drugs, thus reducing potential adverse effects. Local skin adverse effects are limited when compared to those with traditional testosterone patches, but they potentially allow transference of testosterone during close contact with the skin surface. The risk can be reduced by wearing clothing or by applying the gel on skin surfaces not usually touched (e.g., the inner thigh surface) ¹⁰³, ¹⁰⁴. To reduce the total amount of gel applied and residual quantities remaining on the skin, new formulations of testosterone gel have been introduced with a testosterone concentration of 1.62-2% ¹⁰³, ¹⁰⁴. Another transdermal testosterone formulation includes a topical, alcohol-based testosterone (2%) solution, which must be applied to the underarm once daily, using a metered dose applicator ¹⁰³, ¹⁰⁴. Testosterone levels should be monitored to optimize the testosterone dose. Blood collection is best taken two to four hours after gel application to use the peak level of testosterone absorbed as a reference for adequate therapeutic levels. Levels of testosterone after application can vary and a repeat measurement may be indicated especially as sometimes, inadvertently, the skin over the venipuncture site can be contaminated by the gel, leading to falsely elevated results.

In some European countries, dihydrotestosterone (DHT) is available as a hydroalcoholic 2.5% gel. It is rapidly absorbed, reaching a steady state in two to three days ¹⁰³, ¹⁰⁴. Similar to that reported for mesterolone, dihydrotestosterone (DHT) is not aromatised but can be useful for treating particular conditions, such as gynecomastia and microphallus ¹⁰³, ¹⁰⁴.

Testosterone Transmucosal formulations

A testosterone buccal system is still available in several countries. It consists of a sustained-release muco-adhesive buccal-testosterone-tablet requiring twice-daily application to the upper gums. The tablet does not dissolve completely in the mouth and must be removed after twelve hours. This formulation has been proven to restore testosterone levels within the physiological range with minimal or transient local problems, including gum oedema, blistering and gingivitis ¹⁰³, ¹⁰⁴.

A gel for intranasal administration is available in some countries, including the USA and Canada. It requires administration two or three times daily using a specific metered-dose pump. The application is rapid, non-invasive, and convenient, and avoids secondary transference observed with other topical products ¹⁰³, ¹⁰⁴. Preliminary results suggest that intranasal testosterone is associated with lower suppression of gonadotropin levels and with a lower risk of hematocrit increases ¹²³.

Testosterone Subdermal depots

The implantation of testosterone pellets, available in a limited number of countries, represents the longest available testosterone formulation lasting from four to seven months. The procedure is invasive and may be unattractive to patients ¹⁰³, ¹⁰⁴.

Therapies that Increase Endogenous Testosterone

Mechanism of action: Multiple mechanisms of action by affecting various points along the hypothalamic-pituitary-gonadal axis to increase
Types: Selective estrogen receptor modulators (SERMs), Gonadotropins, Aromatase inhibitors, Selective androgen receptor modulators (SARMs), Leydig stem cell transplantation

• Advantages:
  • Able to increase serum and intratesticular testosterone levels
  • Greater likelihood of preserving hypothalamic-pituitary-gonadal axis axis function and, subsequently, spermatogenesis and fertility
• Limitations:
  • Potential unintended decline in quality of semen and complications related to changes in estrogen levels
  • None have been approved by the US FDA specifically for men with hypogonadism or infertility.

Table 3. Therapies that increase endogenous testosterone

Class	Mechanism of Action	Strengths	Limitations	References
Selective Estrogen Receptor Modulators (SERMs)	Mixed estrogen agonist/antagonist properties in different tissues In the pituitary gland, acts as an antagonist, thus stimulating the release of LH and FSH, which drive both testosterone production and spermatogenesis	Successful in treatment of azoospermia, oligospermia, male hypogonadism, and unexplained male infertility	Increased risk of thromboembolic events and carcinogenesis	El Meliegy et al. 2018 124, Chehab et al. 2015 125
Gonadotropins	Mimics effects of endogenous gonadotropins and is particularly useful in the treatment of hypogonadotropic hypogonadism Like endogenous gonadotropins, stimulates testosterone production and spermatogenesis	Successful in treatment of hypogonadal men, while maintaining semen parameters, intratesticular testosterone, and fertility Useful for preserving spermatogenesis in men undergoing exogenous TRT by maintaining intratesticular testosterone levels	Side effects of gynecomastia, headache, fatigue, and mood changes	Lee & Ramasamy 2018 126, El Meliegy et al. 2018 124, Dohle et al. 2016 127
Aromatase Inhibitors	Blocks aromatase conversion of testosterone to estradiol, thereby increasing testosterone levels and normalizing the testosterone/estradiol ratio	Useful in treating infertility in obese men with hypogonadotropic hypogonadism	Potential increase in PSA level in elderly men with low or borderline hypogonadism Limited long-term data to assess efficacy and adverse effects	Crosnoe et al. 2013 128, El Meliegy et al. 2018 124, Ribeiro et al. 2016 129
Selective Androgen Receptor Modulators (SARMs)	Selective agonist of tissue-specific androgen receptors, mimicking the effect of testosterone in certain tissues	Potential use in the treatment of male hypogonadism and infertility	Currently in investigational phase; further studies are required to assess safety and efficacy	Narayanan et al. 2018 130, Solomon et al. 2018 131
Leydig Stem Cell Transplantation	Leydig stem cells can differentiate into adult Leydig cells, which produce intratesticular testosterone under stimulation of LH	Successful studies showing increased testosterone production in various animal models	Further studies are required to prove effectiveness and safety in humans	Zang et al. 2017 132, Beattie et al. 2015 133, Arora et al. 2019 134

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) are a group of pharmaceuticals that act as competitive inhibitors of estrogen receptors in the hypothalamus and pituitary with the increasing release of GnRH and gonadotrophins, subsequently increasing production of intra-testicular testosterone and improving spermatogenesis ¹³⁵. Clomiphene citrate is a SERM that has been used in the treatment of men with azoospermia, oligozoospermia, and unexplained infertility, in addition to treating male hypogonadism. It has been demonstrated that Clomiphene citrate leads to a moderate increase in FSH, LH, total testosterone, and the concentration of sperm in these men ¹³⁶. Also, in men with late-onset hypogonadism, long-term Clomiphene citrate therapy can be prescribed as a testosterone replacement ¹³⁵. Although thromboembolic events and carcinogenesis have been reported as adverse effects of SERMs ¹³⁷, current ongoing research shows that this group of pharmaceuticals has great potential for future applications ¹³⁸.

Gonadotropins

Gonadotropin therapy is used to manage infertile patients with low testosterone concentrations, with the aim of recovering normal sperm production. In such patients, stimulating spermatogenesis requires human chorionic gonadotropin (hCG) therapy alone or in combination with human menopausal gonadotrophins (hMGs), urinary FSH, or recombinant FSH ¹³⁵. It has been recommended that TRT with concomitant use of hCG can be prescribed in hypogonadal men who seek fertility treatment ¹³⁹. Treatment with hCG can preserve normal sperm production in men undergoing TRT by maintaining intratesticular testosterone concentrations ¹⁴⁰. Potential side effects of gonadotropin therapy include gynecomastia, headache, fatigue, and mood changes ¹⁴¹. A retrospective study found that treatment of hypogonadal men with TRT and co-administration of low dose hCG maintains semen parameters in these men ¹⁴². Coviello et al. ¹⁴³ evaluated intratesticular testosterone concentrations from men with normal reproductive physiology who received testosterone enanthate in combination with hCG (125, 250, or 500 IU). A linear increase in intratesticular testosterone concentrations with increased hCG confirms that moderately low dose hCG preserves testicular function in endogenous gonadotropin-suppressed healthy men ¹⁴³. A systematic review showed that hypogonadal men desiring fertility preservation while benefiting from TRT can be prescribed SERMs or testosterone plus a low dose of hCG. Prescription of hCG alone or in combination with FSH preparations can be recommended to hypogonadotropic hypogonadal patients who need to be treated for infertility ¹³⁵. In younger men with low serum testosterone levels, treatment with hCG or with Clomiphene citrate will increase serum and intra-testicular testosterone levels without resulting in declining gonadotropin levels via feedback inhibition ¹²⁸. Overall, human chorionic gonadotropin (hCG) is an efficient and safe alternative or adjunct to TRT in men desiring both fertility and treatment for symptoms of hypogonadism. However, a drawback of hCG is that this is an injectable agent.

Aromatase inhibitors

Aromatase inhibitors are a class of drugs that act by blocking aromatase P450 enzymes, consequently normalizing the testosterone/E2 ratio and improving spermatogenesis ¹²⁴. It has been shown that an aromatase inhibitor (Testolactone) is an effective drug for alleviating infertility in hypogonadotropic hypogonadal obese men ¹²⁵. However, Testolactone is no longer commercially available. Some men with severe spermatogenic failure who have too much aromatase activity, decreased serum levels of testosterone, increased E2 levels, or impaired testosterone/E2 ratio might benefit from the use of aromatase inhibitors in treating infertility ¹³⁵. Although no important side effects have been observed with consumption of an aromatase inhibitor for elevating serum testosterone concentrations (46), one study has reported a slight insignificant increase in the level of serum prostate-specific antigen (PSA) in elderly men with low or borderline hypogonadism ¹⁴⁴. However, the use of aromatase inhibitors is not suggested due to the absence of long-term data and a limited amount of published literature ¹⁴⁵.

Selective androgen receptor modulators

The pathological effects arising from testosterone has resulted in the search for tissue-selective agonists of the androgen receptor which could potentially trigger the androgen receptor in a tissue-selective manner ¹³⁰. Selective androgen receptor modulators (SARMs) are a new class of androgen receptor ligands that bind to androgen receptors, depending on the chemical structure of each SARM. Consequently, SARMs lead to anabolic activity while avoiding most of the side effects caused by anabolic steroids ¹³¹. The tissue specificity of SARMs has led to the notion that they may be a promising treatment for a wide variety of diseases ¹³¹. SARMs have been studied in the treatment of male hypogonadism and their use is being investigated in clinical trials (6, 60). Miner et al. (2007), in a rat model of sexual behavior, showed that SARMs can lead to increased sexual function. In this model treatment of male rats with 100 mg/kg of a synthetic SARM, LGD226, increased number of mounts, intromissions, and ejaculation ¹²⁷. Jones et al. ¹⁴⁶ demonstrated that administration of S-23 with estradiol benzoate in male rats led to inhibition in spermatogenesis and the suppression of FSH and LH levels. However, these effects are completely reversible. Chen et al. ¹⁴⁷ reported that C-6, a novel SARM, can mimic in vivo endocrine effects of testosterone. Administration of C-6 significantly inhibited spermatogenesis and decreased testosterone concentration, epididymal and testicular size (63). Another study showed that SARM-2f, a novel SARM compound, can restore the sexual behavior in castrated male rats ¹⁴⁸. Although SARMs represent an attractive therapeutic approach, further studies are required for the safe use of these medications ¹³¹.

Leydig stem cell transplantation

Adult Leydig cells found in the interstitial space of the testis, are the primary source of testosterone production in males ¹⁴⁹. Adult Leydig cells undergo a four-stage process of differentiation, beginning with undifferentiated mesenchymal cells (also known as Leydig stem cells [LSCs]) and progressing to progenitor Leydig cells, immature Leydig cells, and finally to adult Leydig cells ¹⁵⁰. Leydig stem cells do not have steroidogenic capabilities; however, they are unique in that they are capable of replicating indefinitely and differentiating to functioning adult Leydig cells ¹⁵⁰. This suggests the possibility of having an endless pool of progenitor cells capable of replacing dysfunctional adult Leydig cells and restoring testosterone production in men with low testosterone ¹⁵¹. Arora et al. ¹³⁴ showed that Leydig stem cells in combination with Sertoli and myoid cells underwent self-renewal as well as differentiation into mature Leydig cells. Adult Leydig cells act in the hypothalamic-pituitary-gonadal axis: an increase in LH stimulates the first step of testosterone synthesis in adult Leydig cells; conversely, an increase in testosterone production by adult Leydig cells decreases LH production by the pituitary ¹⁵². Dysfunction at any point along the hypothalamic-pituitary-gonadal axis axis can lead to testosterone deficiency ¹³².

Beattie et al. ¹³³ demonstrated increased testosterone production in rat models by directly stimulating aged adult Leydig cells with translocator protein, a ligand involved in transporting cholesterol from the cytosol to mitochondria. This process was independent of LH regulation and treated aged adult Leydig cells had equivalent testosterone production to young adult Leydig cells. Other studies have shown great promise in increasing testosterone production at more upstream regulation points. Jiang et al. ¹⁵³ showed that transplantation of nestin-positive Leydig stem cells into the testis of mice with impaired adult Leydig cells caused differentiation into functional adult Leydig cells and an increase in testosterone production. Zhang et al. ¹⁰⁸ identified that transplanting human p75+ Leydig stem cells into EDS-treated rats (inducing ALC dysfunction) successfully replaced the impaired adult Leydig cells and partially restored testosterone production. Arora et al. ¹³⁴ demonstrated a novel form of Leydig stem cell transplantation by autografting Leydig stem cells in combination with Sertoli cells and peritubular myoid cells into the subcutaneous, rather than the testicular, tissue of hypogonadal mouse models. This also resulted in differentiation of Leydig stem cells into adult Leydig cells and increased testosterone production ¹³⁴.

Testosterone replacement therapy contraindications

Main contraindications of testosterone therapy:

• Absolute contraindications
  • Locally advanced or metastatic prostate cancer
  • Male breast cancer
  • Men with an active desire to have children
  • Hematocrit ≥ 54%
  • Uncontrolled or poorly controlled congestive heart failure
• Relative contraindication
  • International Prostate Symptom Score (IPSS) > 19
  • Baseline hematocrit 48-50%
  • Familial history of venous thromboembolism

Absolute contraindications to testosterone replacement therapy are untreated breast and prostate cancer. Similarly, conditions such as cardiovascular diseases as well as uncontrolled or poorly controlled congestive heart failure should be considered when prescribing testosterone therapy ¹⁵⁴. Severe lower urinary tract symptoms (LUTS) [International Prostate Symptom Score (IPSS) score > 19] represent a relative contraindication, as there is insufficient data on the long-term effects of testosterone therapy in these patients ⁹⁶. A positive family history for venous thromboembolism requires further analysis to exclude a condition of undiagnosed thrombophilia-hypofibrinolysis ¹⁵⁵. These patients need to be carefully counseled prior to testosterone therapy initiation. An elevated hematocrit (HCT) level is the most common adverse effect of testosterone therapy. Stimulation of erythropoiesis is a normal biological action that enhances the delivery of oxygen to testosterone-sensitive tissues (e.g., striated, smooth and cardiac muscle). Any elevation of hematocrit (HCT) above the normal range for hematocrit usually becomes evident between three and twelve months after testosterone therapy initiation. However, polycythemia can also occur after any subsequent increase in testosterone dose, switching from topical to parenteral administration and, development of comorbidity, which can be linked to an increase in hematocrit (e.g., respiratory or haematological diseases).

A hematocrit (HCT) > 54% should require testosterone therapy withdrawal, reduction in dose, change of formulation and venesection depending on the clinical situation to avoid any potential cardiovascular complications. Lower baseline hematocrit (HCT) (48-50%) should be carefully evaluated before testosterone therapy initiation, to avoid pathological increases during treatment, especially in high-risk men such as those with Chronic Obstructive Pulmonary Disease (COPD) or Obstructive Sleep Apnea (OSA). Accordingly, the Framingham Heart Study showed that hematocrit (HCT) > 48% represented a condition associated with increased risk of coronary artery disease (coronary heart disease) and mortality and was associated with cardiovascular disorders ¹⁵⁶. Testosterone therapy suppresses gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and endogenous testosterone secretion as well as spermatogenesis ¹⁵⁷. Therefore, testosterone therapy is contraindicated in individuals who desire fertility ¹⁵⁸. Secondary hypogonadism is characterised by low or inappropriately normal gonadotropin levels; therefore, the rationale is to substitute the gonadotropin deficiency with simultaneously luteinizing hormone (LH) and follicle-stimulating hormone (FSH) analogues, if fertility is desired ¹⁵⁹.

Testosterone replacement therapy dosage

Adult Male Dose for Hypogonadism

Uses:

• Primary hypogonadism (congenital or acquired): Testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter Syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (FSH, LH) above the normal range.
• Hypogonadotropic hypogonadism (congenital or acquired): Gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range.

IM INJECTION:

• Testosterone Undecanoate: 750 mg (3 mL) IM injection followed by 750 mg (3 mL) injected after 4 weeks, then 750 mg (3 mL) every 10 weeks thereafter
• Testosterone Enanthate and Cypionate: 50 to 400 mg IM injection every 2 to 4 weeks

IMPLANT:

• 2 to 6 pellets (75 mg each) implanted subcutaneously every 3 to 6 months.
• The number of pellets to be implanted depends upon the minimal daily requirements of testosterone propionate administered parenterally. Thus, implant two 75 mg pellets for each 25 mg testosterone propionate required weekly.

Comments:

• The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose.
• This drug should be used only if the benefits outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.
• Injections more frequently than every two weeks are not recommended.
• Adequate effect of the implants (pellets) continues for three to four months, sometimes as long as six months.

BUCCAL:

• Mucoadhesive Oral Patch: Apply a 30 mg patch to the gum region twice a day; morning and evening (about 12 hours apart).

TOPICAL:

• Transdermal Film: 2 to 6 mg applied to the back, abdomen, upper arm, or upper thigh once a day, preferably at night.
• Gel (in tubes, packets or spray): 5 g applied once a day, preferably in the morning. Consult the manufacturer product information for specific dosage and additional instructions of use.
• Transdermal Solution: Initial dose is 60 mg of testosterone (1 pump actuation of 30 mg of testosterone to each axilla), applied once a day, at the same time each morning. Consult the manufacturer product information for specific dosage and additional instructions of use.

Comments: Prior to initiating therapy with this drug, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days, and that these serum testosterone concentrations are below the normal range.

Pediatric Male Dose for Delayed Puberty

Use: To stimulate puberty in selected males with clearly delayed puberty

IM INJECTION:

• Testosterone Enanthate: 50 to 200 mg every 2 to 4 weeks for 4 to 6 months

IMPLANT:

• 2 pellets (each pellet contain 75 mg of testosterone) implanted subcutaneously every 3 to 6 months
• Duration of therapy: 4 to 6 months

Comments:

• The chronological and skeletal ages should be taken into consideration when determining the initial dose and when adjusting the dose.
• An X-ray of the hand and wrist to determine bone age should be obtained every six months to assess the effect of treatment on the epiphyseal centers.
• Report frequent or persistent erections.
• Androgen therapy should be used very cautiously in children and only by specialists who are aware of the adverse effects on bone maturation.

Renal Dose Adjustments

• Testosterone Cypionate IM injection: Contraindicated in renal disease

Liver Dose Adjustments

• Testosterone Cypionate IM injection: Contraindicated in liver disease

Dose Adjustments

• The doses of this drug should be adjusted according to the patient’s response and the appearance of adverse reactions.

Testosterone replacement therapy monitoring

Testosterone replacement therapy alleviates symptoms and signs of hypogonadism in men in a specific time-dependent manner ³. The results of testosterone clinical trials showed that testosterone therapy improved sexual symptoms as early as 3 months after initiation ¹⁶⁰, ¹⁵⁵, ¹⁶¹. Table 2 summarises the clinical and biochemical parameters that should be monitored during testosterone therapy. The first evaluation should be planned after 3 months of testosterone treatment. Further evaluation may be scheduled at 6 months or 12 months, according to patient characteristics, as well as results of biochemical testing. Patients at high risk of developing elevated hematocrit should be evaluated every 3 months during the first year of testosterone therapy and at least every 6 months thereafter. Accordingly, current guidelines suggest that hematocrit should be maintained below 45% in patients with polycythemia vera to avoid thromboembolism risk ¹⁶². Similarly, data derived using a multi-institutional database including a large cohort of hypogonadal (total testosterone < 12 nmol/L) men who received testosterone therapy and subsequently did (n=5,887) or did not (n=4,2784) develop polycythemia (hematocrit > 52%) showed that men who had an increased hematocrit had a higher risk of major adverse cardiovascular events or venous thromboembolism mostly during the first year of therapy ¹⁶³. The risk was even higher when a hematocrit threshold of 54% was considered whilst no risk was observed when a hematocrit 50% threshold was applied ¹⁶³.

Testosterone Trials were designed to maintain the serum testosterone concentration within the normal range for young men (280–873 ng/dL or 9.6-30 nmol/L) ¹⁶⁰. This approach resulted in a good benefit/risk ratio. A similar approach could be considered during follow-up. The correct timing for the evaluation of testosterone levels varies according to the type of testosterone preparation used. Testosterone is involved in the regulation of erythropoiesis ¹²¹ and prostate growth ⁹², hence measuring serum PSA and hematocrit should be mandatory before and during testosterone therapy. However, it is important to recognize that the risk of prostate cancer in men aged < 40 years is low. Similarly, the mortality risk for prostate cancer in men aged > 70 years has not been considered high enough to warrant monitoring in the general population ¹⁶⁴. Therefore, any screening for prostate cancer through the determination of PSA and digital rectal exam (DRE) in men aged < 40 or > 70 years during testosterone therapy should be discussed with the patients.

Baseline and annual metabolic profile evaluation may be a reasonable consideration, particularly in the management of functional hypogonadism. Testosterone therapy may be beneficial for hypogonadal men with low or moderate fracture risk ¹⁶⁵. Therefore, dual energy X-ray absorptiometry (DEXA) bone scan may also be considered at baseline and 18-24 months following testosterone therapy, particularly in patients with more severe hypogonadism ¹⁶⁵.

Digital rectal examination (DRE) may detect prostate abnormalities that can be present even in men with normal PSA values. Hence, digital rectal exam (DRE) is mandatory in all men at baseline and is recommended to be performed at least annually during testosterone therapy, as long as there is no significant increase in PSA velocity.

The decision to stop testosterone therapy or to perform a prostate biopsy due to PSA increase or prostate abnormalities should be based on local prostate cancer guidelines. There is a large consensus that any increase of hematocrit > 54% during testosterone therapy requires testosterone withdrawal and phlebotomy to avoid potential adverse effects including venous-thromboembolism and cardiovascular disease, especially in high-risk individuals ³. In patients with lower risk of relevant clinical complications, the situation can be alternatively managed by reducing testosterone dose and switching formulation along with venesection ³. A positive family history of venous-thromboembolism should be carefully investigated and the patient counseled about testosterone therapy to avoid/prevent thrombophilia-hypofibrinolysis ¹⁵⁵. Finally, caution should be exercised in men with pre-existing cardiovascular disease or at higher risk of cardiovascular disease ¹⁵⁴.

Table 2. Clinical and biochemical parameters to be checked during testosterone therapy

Parameters		Year 1 of treatment			After year 1 of treatment
	Baseline	3 months	6 months	12 months	Annually	18-24 months
Clinical
Symptoms	X	X	X	X	X
Body Mass Index	X			X	X
Waist circumference	X	X		X	X
Digital rectal examination	X			X	X
Blood pressure	X	X		X	X
Biochemistry
PSA (ng/mL)	X	X	X2	X	X
Hematocrit (%)	X	X	X1,2	X	X
Testosterone	X	X		X	X
Lipid and glycaemic profile	X			X	X
Instrumental
DEXA	X					X

Footnotes: 1) Population with polycythemia vera or at high risk of secondary polycythemia (e.g., sleep apnea, morbidobesity, heavy smokers, chronic obstructive pulmonary disease); 2) Prostate cancer survivors.

[Source ³ ]

Testosterone replacement therapy risks

Testosterone replacement therapy has various risks. For example, testosterone therapy may:

• Elevate red blood cell count (erythrocytosis), thereby increasing the risk of blood clots or venous thromboembolism ¹⁶⁶
• Cause acne or other skin reactions
• Contribute to sleep apnea — a potentially serious sleep disorder in which breathing repeatedly stops and starts
• Stimulate noncancerous growth of the prostate (benign prostatic hyperplasia) and growth of existing prostate cancer
• Enlarge breasts
• Limit sperm production or cause testicle shrinkage
• Increase the risk of a blood clot forming in a deep vein (deep vein thrombosis), which could break loose, travel through your bloodstream and lodge in your lungs, blocking blood flow (pulmonary embolism)

In addition, testosterone therapy may impact your risk of heart disease. Research has had conflicting results, so the exact risk isn’t clear yet. Most notable are  the TOM (Testosterone in Older Men) trial and the TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) trials. Low testosterone levels have been associated with increased risk of coronary artery disease ¹⁶⁷. Published in JAMA 2017, a study ¹⁶⁸ found that testosterone replacement was associated with a lower risk of cardiovascular outcomes. In 2015, the FDA concluded a possible increased cardiovascular risk associated with testosterone use requiring labeling change to inform the public. The FDA requires that you are made aware that the possibility of cardiovascular events may exist during treatment.

The American Association of Clinical Endocrinologists ¹⁶⁹ issued a guideline in response to the 2015 FDA labeling requirement on cardiovascular risk and stated that there is no compelling evidence that testosterone therapy increases cardiovascular risk. On the other hand, testosterone deficiency has been associated with falls, sarcopenia, frailty, osteopenia, and osteoporosis ¹⁷⁰.

Serum PSA levels can increase in response to testosterone treatment, so it is important to rule out prostate cancer before starting therapy as it can worsen the disease process. Patients on replacement therapy need to be reevaluated for prostate cancer at 3 months and 1 year after beginning treatment ¹⁷¹.

There is no firm scientific evidence that long-term testosterone replacement is associated with either prostate cancer or cardiovascular events. Prostate cells are stimulated by testosterone, so be extra vigilant about cancer screenings. African American men over age 45 — especially those with family history of cancer — are already at risk for prostate cancer.

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