Late onset hypogonadism

Late-onset hypogonadism has been used to describe those patients with an age-related decline in serum testosterone levels, and the most prevalent symptoms are those of sexual dysfunction, particularly decreased morning erections, reduced sexual thoughts, and erectile dysfunction ¹. Additional terms such as andropause, viropause, partial androgen deficiency of the ageing man, and testosterone deficiency syndrome have all been used to describe late-onset hypogonadism. Male hypogonadism is characterized by serum testosterone levels < 300 ng/dL in combination with at least one clinical sign or symptom ². The International Society of Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM) and the European Association of Urology (EAU) attempted to standardize terminology in 2008 and defined late-onset hypogonadism as a “clinical and biochemical syndrome associated with advancing age and characterised by typical symptoms and deficiency in serum testosterone levels” ³. Within these guidelines, there was no accepted lower limit for normal, but the consensus was that total testosterone levels above 12 nmol/L (350 ng/dL) do not require testosterone replacement but that men with total serum testosterone levels of less than 8 nmol/L (230 ng/dL) will usually benefit from treatment. These “typical” symptoms are not clearly defined but include erectile dysfunction, mood or cognitive disturbance, muscle weakness, osteoporosis, and body hair and skin changes. The scientific rationale for the aforementioned definition was based on available scientific data on androgen supplementation therapy and, by their own omission, should be regarded as provisional until higher-level evidence becomes available. Interestingly, they do note that “a correlation between low serum testosterone levels in elderly men and erectile dysfunction has still to be conclusively demonstrated” ³.

Interest in late-onset hypogonadism has been reported since the mid-20th century. Heller and Myers ⁴ described the “male climateric” but noted that it was infrequent and a pathologic accompaniment of the ageing process. There has been a renewed interest in hypogonadism given improvements in testosterone replacement preparations, the rise in life expectancy, and a recent vogue for male rejuvenation treatments. Moreover, there is evidence that testosterone deficiency is associated with metabolic syndrome and potentially a long-term increase in cardiovascular mortality ⁵. Therefore, it has been suggested that treatment can encourage weight loss and offset the deleterious long-term cardiovascular risks of metabolic syndrome. However, late-onset hypogonadism has recently been placed under scrutiny given the widespread use of testosterone replacement therapy; in 2011, the global sales of testosterone reached an estimated $1.8 billion ⁶. In addition to this, safety concerns related to the possible increased cardiovascular risk associated with the use of testosterone replacement therapy have been raised. Indeed, owing to the media and scientific scrutiny of testosterone replacement therapy, there has been a surge of petitioning to the US Food and Drug Administration (FDA) to enforce warnings on medication packaging ⁷.

Male aging facts ⁸:

• Testosterone production/ levels decrease gradually beginning around age 30
• Sperm production does not stop
• Not all men experience low testosterone and sperm production

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

Testosterone is the most important sex hormone that men have. Throughout men’s lifespan, testosterone plays a critical role in sexual, cognitive, and body development. During fetal development, testosterone aids in the determination of sex. The most visible effects of rising testosterone levels begin in the prepubertal stage. During this time, body odor develops, oiliness of the skin and hair increase, acne develops, accelerated growth spurts occur, and pubic, early facial, and axillary hair grows. In men, the pubertal effects include enlargement of the sebaceous glands, penis enlargement, increased libido, increased frequency of erections, increased muscle mass, deepening of voice, increased height, bone maturations, loss of scalp hair, and growth of facial, chest, leg, and axillary hair. Even as adults, the effects of testosterone are visible as libido, penile erections, aggression, and mental and physical energy.

Testosterone 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.

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.

Testosterone facts 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.

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

What causes low testosterone?

Low testosterone can result from:

• Testicular injury (trauma, castration) or infection
• Radiation or chemotherapy treatment for cancer
• Some medications, such as opiate painkillers Hormone disorders (pituitary tumors or diseases, high levels of prolactin)
• Chronic diseases, such as liver and kidney disease, obesity, type 2 diabetes, and HIV/AIDS
• A genetic condition (Klinefelter syndrome, hemochromatosis, Kallmann syndrome, Prader-Willi syndrome, myatonic dystrophy)
• Anabolic Steroid use in the past
• In many cases, the cause is not known.

Low testosterone is common in older men. An accurate blood test needs to be done in the morning between 7am-10am.

How is low testosterone treated?

Testosterone replacement therapy can improve sexual interest, erections, mood and energy, body hair growth, bone density, and muscle mass. There are several ways to replace testosterone:

• Gel or patches that you put on your skin
• Injections (shots)
• Tablets that stick to the gums
• Pellets inserted under the skin or pills (in some countries outside the United States)

The best method will depend on your preference and tolerance, and the cost.

There are risks with long-term use of testosterone. The most serious possible risk is prostate cancer. African American men, men over 40 years of age who have close relatives with prostate cancer, and all men over 50 years of age need monitoring for prostate cancer during testosterone treatment. Men with known or suspected prostate cancer, or with breast cancer, should not receive testosterone treatment.

Other possible risks of testosterone treatment include:

• A high red blood cell count
• Acne
• Breast enlargement
• An increase in prostate enlargement
• Sleep apnea—the occasional stopping of breathing during sleep (rarely)
• Fluid buildup (edema) in ankles, feet and legs (rarely)

Male hypogonadism classification

Male hypogonadism means the testicles don’t produce enough of the male sex hormone testosterone.

There are two basic types of male hypogonadism that exist:

• Primary male hypogonadism: This type of hypogonadism – also known as primary testicular failure – originates from a problem in the testicles.

• Secondary male hypogonadism: 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 the gonadotropin releasing hormone, which signals the pituitary gland to make the follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The luteinizing hormone then signals the testes to produce testosterone. Either type of hypogonadism may be caused by an inherited (congenital) trait or something that happens later in life (acquired), such as an injury or an infection.

Primary Hypogonadism

Common causes of primary hypogonadism include:

Klinefelter’s Syndrome

This condition results from a congenital abnormality of the sex chromosomes, X and Y. A male normally has one X and one Y chromosome. In Klinefelter’s syndrome, two or more X chromosomes are present in addition to one Y chromosome (46,XXY). The Y chromosome contains the genetic material that determines the sex of a child and the related development. The extra X chromosome that occurs in Klinefelter’s syndrome causes abnormal development of the testicles, which in turn results in the underproduction of testosterone.

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 may not descend at birth. This condition often corrects itself within the first few years of life without treatment. If not corrected in early childhood, it may lead to malfunction of the testicles and reduced production of testosterone.

Mumps orchitis

If a mumps infection involving the testicles in addition to the salivary glands (mumps orchitis) occurs during adolescence or adulthood, long-term testicular damage may occur. This may affect normal testicular function 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 of their location outside the abdomen, the testicles are prone to injury. Damage to normally developed testicles can cause male hypogonadism. Damage to one testicle may not impair 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 are often temporary, but permanent infertility may occur. Although many men regain their fertility within a few months after the treatment ends, preserving sperm before starting cancer therapy is an option that many men consider. Howell et al. ⁹ reported that hypogonadism was seen in 30% of the men with cancer and 90% of these gentlemen had germinal epithelial failure.

Normal aging

Older men generally have lower testosterone levels than younger men do. As men age, there’s a slow and continuous decrease in testosterone production. The rate that testosterone declines varies greatly among men. As many as 30% of men older than 75 have a testosterone level that is below normal, according to the American Association of Clinical Endocrinologists. Whether or not treatment is necessary remains a matter of debate ¹⁰.

Secondary Hypogonadism

In secondary hypogonadism, the testicles are normal, but function improperly due to a problem with the pituitary or hypothalamus. A number of conditions can cause secondary hypogonadism, including:

Kallmann syndrome

Abnormal development of the hypothalamus – the area of the brain that controls the secretion of pituitary hormones – can cause hypogonadism. This abnormality is also associated with the impaired development of the ability to smell (anosmia) and 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, the treatment for a brain tumor such as surgery or radiation therapy may impair pituitary function and cause hypogonadism.

Inflammatory disease

Certain inflammatory diseases such as sarcoidosis, histiocytosis, and tuberculosis involve the hypothalmus and pituitary gland and can affect testosterone production, causing hypogonadism.

HIV/AIDS

This virus 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 ¹¹.

Obesity

Being significantly overweight at any age may be linked to hypogonadism.

Stress-induced Hypogonadism

Stress, excessive physical activity, and weight loss have all been associated with hypogonadism. Some have attributed this to stress-induced hypercortisolism, which would suppress hypothalamic function ¹².

Risk factors for male hypogonadism

Risk factors for hypogonadism include:

• Kallmann syndrome
• Undescended testicles as an infant
• Mumps infection affecting your testicles
• Injury to your testicles
• Testicular or pituitary tumors
• HIV/AIDS
• Klinefelter syndrome
• Hemochromatosis
• Previous chemotherapy or radiation therapy
• Untreated sleep apnea

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

Late onset hypogonadism symptoms

Signs of hypogonadism include absence or regression of secondary sex characteristics, anemia, muscle wasting, reduced bone mass or bone mineral density, oligospermia, and abdominal adiposity. Symptoms of late onset hypogonadism include sexual dysfunction (erectile dysfunction, reduced libido, diminished penile sensation, difficulty attaining orgasm, and reduced ejaculate), reduced energy and stamina, depressed mood, increased irritability, difficulty concentrating, changes in cholesterol levels, anemia, osteoporosis, and hot flushes.

Possible symptoms of low testosterone:

• Reduced energy
• Enlargement of breasts
• Loss of body hair
• Decline in sexual function (erectile dysfunction, decreased morning erections, reduced sexual thoughts, reduced sex drive)
• Decreased bone density
• Increased body fat/reduced muscle
• Hot flashes (rare)
• Irritability; trouble remembering; trouble concentrating; depression

Not all men experience these symptoms. However, ones who do, encounter them for no apparent reason other than age, usually advanced age.

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

• Drop in sex drive (libido)
• Erectile dysfunction (inability to get or keep an erection) and loss of spontaneous erections
• Lowered sperm count and infertility (inability to have children)
• Breast enlargement (gynecomastia) 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)
• Loss of bone mass (osteoporosis)

Hypogonadism can also cause mental and emotional changes. As testosterone decreases, some men may experience symptoms similar to those of menopause in women. These may include:

• Fatigue
• Decreased sex drive
• Difficulty concentrating

Late-onset hypogonadism most prevalent symptoms are those of sexual dysfunction, particularly decreased morning erections, reduced sexual thoughts, and erectile dysfunction ¹. Sexual dysfunction is a broad term which encompasses several symptoms, including erectile dysfunction, premature or delayed ejaculation, and low libido. Male sexual function is dependent on several factors, including hormone levels, general fitness, sexual desire, psychological elements as well as the current state of the couple’s relationship ¹³.

Many other studies have shown that sexual frequency decreases with age. Given the complex nature of sexual dysfunction, it is difficult to isolate whether this is a physiological, psychological or pathological consequence of ageing ¹. Moreover, if you were to assume it was pathological, several comorbidities (including drugs) could be attributable. A number of studies have demonstrated the association between late-onset hypogonadism and male sexual dysfunction ¹⁴.

Late onset hypogonadism diagnosis

The diagnosis of late-onset hypogonadism relies on a combination of blood tests and clinical features ³. Your doctor will also use blood tests to see if your total testosterone level is low. This is because men with symptoms of sexual dysfunction and late-onset hypogonadism often have a normal testosterone and some asymptomatic patients may have reduced testosterone.

Your doctor will conduct a physical exam during which he or she will examine your body hair, breasts, muscle mass, 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.

Doctors base a diagnosis of male hypogonadism on symptoms and results of blood tests that measure testosterone levels. Because testosterone levels vary and are generally highest in the morning, blood testing is usually done early in the morning between 7am-10am. Circulating testosterone levels are subject to circadian variation, so blood testing should be performed in the morning. Furthermore, levels of serum testosterone decrease by 25% following glucose ingestion, so fasting samples are most reliable ¹⁵. Furthermore, studies have demonstrated that testosterone measurements can vary greatly. Swerdloff ¹⁶ noted that 18% of patients who had a normal average testosterone level over 24 hours had single or multiple hypogonadal readings. Hence, usually at least two measurements are required to confirm the diagnosis of hypogonadism.

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.

The European Association of Urology, International Society for the Study of the Aging Male (ISSAM) and International Society of Andrology (ISA) recommendations are that a total serum testosterone greater than 12 nmol/L does not require substitution ¹⁷. However, there is no universal agreement on the lower limits of normal testosterone measurements. Sansone et al. ¹⁸ argue that levels below 8 nmol/L are widely considered to require treatment but that levels between 8 and 12 nmol/L represent a grey area where the effects of testosterone are dependent on the patient’s sensitivity to androgens. In this grey area, the authors recommend repeating the total testosterone and also calculating the free testosterone by the combination of total testosterone and sex hormone binding globulin (SHBG) ¹⁹. When hypogonadism is confirmed, prolactin and gonadotropin (follicle stimulating hormone [FSH] and luteinizing hormones [LH]) levels should be measured to exclude hyperprolactinemia and to better characterise the origin of the problem (i.e is it, primary or secondary?).

If tests confirm you have low testosterone, further testing can determine if a testicular disorder or a pituitary abnormality is the cause. Based on specific signs and symptoms, additional studies can pinpoint the cause. These studies may include:

• Hormone testing
• Semen analysis
• Pituitary imaging
• Genetic studies
• Testicular biopsy

Testosterone testing also plays an important role in managing male hypogonadism. This helps your doctor determine the right dosage of medication, both initially and over time.

Late onset hypogonadism treatment

Treatment for male hypogonadism depends on the cause and whether you’re concerned about fertility.

Conservative management

As reported above, obesity is frequently associated with late-onset hypogonadism. Camacho et al. ²⁰ noted that weight loss can reverse the age-related decline in testosterone and free testosterone. Moreover, they demonstrated that, when adjusting forpotential cofounders, a weight decrease of at least 10% led to an increase in testosterone (2.9 nmol/L) and sex hormone binding globulin (SHBG) (13.6 nmol/L).

Corona et al. ²¹ performed a meta-analysis of 24 studies reviewing the impact of weight loss on testosterone levels. In this study, weight loss was associated with a relevant increase in gonadotropins and in bound and unbound testosterone, with a decline in the estrogen level. The testosterone rise was greater with more weight loss. The above evidence highlights the importance of first trialing lifestyle changes in order to facilitate weight loss and thus avoid the potential side effects related to testosterone replacement therapy .

There is an ongoing debate with regard to the impact of improvements in sleep quality and duration on serum testosterone. Wittert ²² noted that although some studies ²³ have shown that treatment of obstructive sleep apnea (OSA) can improve serum testosterone levels, many others have shown equivocal results. Moreover, when age and obesity are adjusted for, OSA (obstructive sleep apnea) appears to have no direct effect on serum testosterone. Rather than duration of sleep, the timing of sleep seems to be more important on testosterone levels. Schmid et al. ²⁴ noted that 4.5 hours of sleep restricted to the first half of the night markedly decreased morning testosterone.

Studies have identified that the use of phosphodiesterase-5 (PDE5) inhibitors  (e.g., sildenafil, vardenafil, tadalafil and avanafil) can improve erectile function in hypogonadal patients ²⁵ and can increase serum testosterone levels ²⁶.

Therefore, Grossmann and Matsumoto ²⁷ argue that first-line management should incorporate lifestyle measures as they have the potential to improve testosterone levels and negate the need for testosterone replacement therapy. Moreover, this should be accompanied by evidence-based management of the clinical problem which would include treating any erectile dysfunction with a phosphodiesterase-5 (PDE5) inhibitor.

Human chorionic gonadotropin

Human chorionic gonadotropin (hCG) stimulates Leydig cells to produce testosterone without impairing spermatogenesis. Studies have demonstrated that hCG can improve testosterone and induce spermatogenesis in hypogonadotrophic hypogonadism patients ²⁸. Moreover, when low-dose hCG is used in conjunction with exogenous testosterone, it provides a protective effect for intratesticular spermatogenesis and sperm counts are maintained ²⁹.

Selective oestrogen receptor modulators

Selective oestrogen receptor modulators (SERMs) have been shown to stimulate estrogen receptors and thereby increase the production of gonadotropins and subsequently testosterone. A meta-analysis ³⁰ demonstrated that selective oestrogen receptor modulators were associated with a statistically significant increased pregnancy rate compared with controls (pooled odds ratio 2.42) and a significant increase in sperm concentration (weighted mean difference 5.24).

Clomiphene citrate has been demonstrated to increase testosterone but also improve hypogonadal symptoms ³¹. However, one study indicated that the use of clomiphene citrate is less effective than testosterone replacement therapy at increasing serum testosterone levels and improving hypogonadal symptoms and libido ³². Enclomiphene citrate is a shorter-acting preparation of clomiphene citrate that has been shown to improve sperm counts but also testosterone levels equivalent to exogenous testosterone ³³.

Aromatase inhibitors

Aromatase inhibitors prevent the conversion of estradiol and therefore prevent the negative feedback effect of estradiol on the hypothalamic–pituitary–gonadal axis, thereby increasing testosterone levels ³⁴. Leder et al. ³⁵ demonstrated that the use of anastrozole significantly increased serum testosterone levels but had no significant effect on erectile function compared with control groups. Aromatase inhibitors can commonly cause hot flashes, night sweats, weight gain, insomnia, myalgia and arthralgia. Moreover, patients are at increased risk of osteopenia ³⁴.

Testosterone replacement therapy

Following a trial of conservative management, testosterone replacement can be commenced. The evidence supporting the use of both a PDE5 inhibitor and testosterone replacement to improve erectile dysfunction is ambiguous ³⁶.

Prior to the start of testosterone replacement therapy, prostate-specific antigen (PSA), haematocrit, digital rectal examination and cardiovascular risk assessment should be performed. The European Association of Urology guidelines ³⁷ recommend that treatment be assessed at 3, 6 and 12 months and annually thereafter. Furthermore, the European Association of Urology states that there is insufficient evidence to define an optimum serum testosterone level. At these intervals, repeat PSA and hematocrit should be measured; if hematocrit levels increase above 0.54, then dose adjustment or discontinuation is suggested along with phlebotomy. The European Association of Urology guidelines do not specify a precise PSA level that mandates investigation but rather that “subjects with a substantial or continuous increase in PSA level need to be investigated to exclude prostate cancer” ³⁷. The International Society for Sexual Medicine ³⁸ has similar recommendations and monitoring periods but stipulates that a PSA increase of 1.4 ng/nL within 1 year or a PSA velocity of more than 0.4 ng/mL necessitates further investigation.

Types of testosterone replacement therapy

Testosterone replacement therapy is the primary treatment option for hypogonadism. Ideally, the therapy should provide physiological testosterone levels, typically in the range of 300 to 800 ng/dL. According to the guidelines from the American Association of Clinical Endocrinologists ³⁹, the goals of therapy are to:

1. Restore sexual function, libido, well-being, and behavior
2. Produce and maintain virilization
3. Optimize bone density and prevent osteoporosis
4. In elderly men, possibly normalize growth hormone levels
5. Potentially affect the risk of cardiovascular disease
6. In cases of hypogonadotropic hypogonadism, restore fertility ⁴⁰

To achieve these goals, several testosterone delivery systems are currently available in the market. Clinical guidelines published in 2006, by the Endocrine Society ⁴⁰, recommend reserving treatment for those patients with clinical symptoms, rather than for those with just low testosterone levels.

Method of treatment depends on the cause of low testosterone, the patient’s preferences, cost, tolerance, and concern about fertility.

• Injections. Testosterone injections sold as Depo-Testosterone (testosterone cypionate) and Delatestryl (testosterone enanthate) are safe and effective. Injections are given in a muscle. Your symptoms might fluctuate between doses depending on the frequency of injections. Self or doctor administered in a muscle every 1–2 weeks; administered at a clinic every 10 weeks for longer-acting. Testosterone undecanoate (Aveed), an injection recently approved by the Food and Drug Administration, is injected less frequently but must be administered by a health care provider and can have serious side effects. The testosterone is suspended in oil to prolong absorption. Peak levels occur within 72 hours of administration, but intramuscular administration is associated with the most variable pharmacokinetics of all the formulations. In the first few days after administration, supraphysiological testosterone levels are achieved, followed by subphysiological levels near the end of the dosing interval. Such fluctuations, are often associated with wide variations in mood, energy, and sexual function, and prove distressing to many patients. To reduce fluctuations, lower doses and shorter dosing intervals (two weeks) are often used. Injection site reactions are also common, but are rarely the reason for discontinuation of therapy. Despite the fluctuations in testosterone levels, intramuscular injections provide a cost-effective option and the convenience of two- to four-week dosing intervals. Disadvantages associated with injections include visits to the doctor’s office, visits for dose administration, and lack of physiological testosterone patterns.
  Side effects: uncomfortable, fluctuating symptoms.
• Gels/Solutions. There are several gel preparations available with different ways of applying them. Depending on the brand, you either rub testosterone gel into your skin on your upper arm or shoulder (AndroGel, Testim, Vogelxo), apply with an applicator under each armpit (Axiron) or pump on your front and inner thigh (Fortesta). As the gel dries, your body absorbs testosterone through your skin. Gel application of testosterone replacement therapy appears to cause fewer skin reactions than patches do. Don’t shower or bathe for several hours after a gel application, to be sure it gets absorbed. Application in the morning allows for testosterone concentrations that follow the normal circadian pattern. Topical testosterone gels also provide longer-lasting elevations in serum testosterone, compared to transdermal patches ⁴¹. Similar to patches, testosterone delivered via gels does not undergo first-pass metabolism. Adverse effects associated with therapy include headache, hot flushes, insomnia, increased blood pressure, acne, emotional labiality, and nervousness. Although application site reactions occur, skin irritation is approximately 10 times less frequent with gels than with transdermal patches ⁴². Advantages associated with topical gel include maintenance of normal diurnal testosterone levels and documented increases in bone density ⁴³. Potential problems associated with the gel are the potential for transfer of the gel from person to person and the cost.A potential side effect of the gel is the possibility of transferring the medication to another person and must wait to absorb completely into skin. Avoid skin-to-skin contact until the gel is completely dry or cover the area after an application.
• Patches. A patch containing testosterone (Androderm) is applied each night to your back, abdomen, upper arm or thigh. The site of the application is rotated to maintain seven-day intervals between applications to the same site, to lessen skin reactions.
• Side effects: skin redness and rashes. Application site reactions account for the majority of adverse effects associated with transdermal patches, with elderly men proving particularly prone to skin irritation. Local reactions include pruritus, blistering under the patch, erythema, vesicle formation, indurations, and allergic contact dermatitis. Approximately 10% of the patients discontinue patch therapy due to skin reactions ⁴⁴. In one study, 60% of the subjects discontinued the patch between weeks four and eight due to skin irritation ⁴⁵. A small percentage of patients may also experience headache, depression, and gastrointestinal (GI) bleeding. Some patients report that the patch easily falls off and is difficult to remove from the package without good dexterity. Transdermal patches are more expensive than injections, but the convenience of use and maintenance of normal diurnal testosterone levels are advantageous. Some patients report that the patch is noisy and therefore they feel stigmatized by its presence.

• Buccal Tablets. A small putty-like substance, gum and cheek testosterone replacement (Striant) delivers testosterone through the natural depression above your top teeth where your gum meets your upper lip (buccal cavity). This product quickly sticks to your gumline and allows testosterone to be absorbed into your bloodstream. Sticky pill applied to gums twice a day, absorbs quickly into bloodstream through gums. With this route, the peak testosterone levels are rapidly achieved and a steady state is reached by the second dose following twice-daily dosing. Similar to gel and transdermal products, buccal administration avoids first-pass metabolism. Food and beverage do not alter drug absorption. Although well-tolerated, transient gum irritation and a bitter taste are the chief adverse effects associated with this route. Gum irritation tends to resolve within the first week. Other adverse effects include dry mouth, toothache, and stomatitis. Some patients find the buccal tablet uncomfortable and report concern about the tablet shifting in the mouth while talking. Side effects: gum irritation.
• Pellets. Testosterone-containing pellets (Testopel) are 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), scarring, dose decreasing over time and male hypogonadism symptoms possibly returning towards the end of dose period.
• Nasal Gel. Testosterone can be pumped into the nostrils as a gel. 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 may be more inconvenient than other delivery methods. Side effects: nasal irritation or congestion.

Oral Tablets

Oral testosterone tablets, under the brand name Andriol, are available in other countries. Android and Testroid – both methyl testosterone products are FDA approved oral formulations.

• Oral testosterone isn’t recommended for long-term hormone replacement because it might cause liver problems.

Although relatively inexpensive, oral products undergo extensive first-pass metabolism and therefore require multiple daily doses. Oral products are associated with elevated liver enzymes, GI intolerance, acne, and gynecomastia. Regardless of the treatment option, patients should be aware of the risks associated with testosterone therapy, including:

• Worsening of the prostatic hypertrophy
• Increased risk of prostate cancer
• Lower sperm count with large doses
• Swelling of ankles, feet, or body, with or without heart failure
• Gynecomastia
• Sleep apnea
• Blood clots

Patients should be educated on the signs and symptoms of these adverse effects and instructed to notify their doctor if any of these occur.

Risks of Testosterone Therapy

• Elevated red blood cell count
• Blood clots forming in the veins
• Acne
• Sleep apnea
• Possible prostate and/or breast enlargement

There is no firm scientific evidence that long-term testosterone replacement is associated with either prostate cancer or cardiovascular events. Recent research also suggests testosterone therapy might increase your risk of a heart attack. The FDA requires that you are made aware that the possibility of cardiovascular events may exist during treatment. 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.

Infertility

The use of exogenous testosterone causes a negative feedback mechanism in the hypothalamic–pituitary–gonadal pathway resulting in reduced intratesticular testosterone and subsequent impaired spermatogenesis. This mechanism has been demonstrated to be both dose- and duration-dependent ⁴⁶. Current understanding of the impact of exogenous testosterone on spermatogenesis is from data on trials using testosterone as a male contraceptive. A dose of 200 mg testosterone enanthate weekly by intramuscular injection induced azoospermia at a mean time of 120 days ⁴⁷ . Liu et al. ⁴⁸ compared 30 studies evaluating the time of sperm recovery and noted that the typical probabilities of recovery to 20 million per millilitre were 67% within 6 months, 90% within 12 months, and 100% within 24 months.

However, other studies have suggested that the side effects of exogenous testosterone may be longer-lasting with a proportion of patients not returning to baseline ⁴⁹.

References

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