State-of-the-Art Update on Testosterone Replacement: A Clinical and Pharmacological Approach

Brought to you through an unrestricted educational grant from Columbia Laboratories Inc.

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Review the prevalence and epidemiology of low-testosterone states in men and the pathophysiology and hormonal regulation of testosterone.
• Be familiar with the signs and symptoms associated with low testosterone state and the concept of andropause.
• Discuss causes of hypogonadism and secondary hypogonadism.
• Understand testosterone delivery systems, including the advantages and disadvantages of each.
• Apply the pharmacy care approach to testosterone-replacement delivery systems with respect to patient counseling, comparison of medications, risks and benefits of therapy, and medication monitoring.

Mankind is constantly searching for a fountain of youth, vitality, and quality of life. One of the most controversial areas in modern day medicine is the concept of hypogonadism (low-testosterone states in men) and its effect on health. This is in part a result of the longevity of men in America: in the Victorian era, men lived an average of 45 years; today, the average male life expectancy is exceeding 75 years. It has been well recognized that testosterone is associated with an increase in libido and erectile function, body muscle mass and strength, bone mineral density, stability, and an increase in energy and a sense of well-being. The progressive decrease in testosterone as men age is being challenged by therapeutic modalities to normalize this important hormone. This article will review the evidence and science related to hypogonadal conditions and the therapeutic options available.

Testosterone decreases in men as they age. The concept is well recognized in the literature, but the rationale and evidence to replace testosterone are new and somewhat controversial. Pharmacists in the front line of health care delivery need to be aware of this growing area of science and the clinical implications for treatment using nondrug, pharmacological, and herbal therapy.

Hypogonadism and Andropause

Low-testosterone states are associated with a syndrome in men akin to menopause in women called andropause (male menopause). The syndrome has also been referred to as male climacteric, viropause, low-testosterone syndrome, androgen deficiency in the aging male (ADAM), partial androgen deficiency in the aging male (PADAM), and aging-associated androgen deficiency (AAAD).¹

The clinical results of low-testosterone state manifest as a collection of symptoms and signs composed of a constellation of physical, sexual, and emotional symptoms brought about by a complex interaction of hormones, psychiatric situations, and physical factors (Table 1).

Physical symptoms associated with male hypogonadism include fatigue, muscle weakness, decreased bone mineral density leading to osteoporosis, changes in fat distribution, and impaired hematopoiesis. Furthermore, the sexual and emotional symptoms include decreased libido, erectile dysfunction, oligospermia, depression, anxiety, irritability, insomnia, memory impairment, and cognitive dysfunction.² It has been postulated that replacement of testosterone will decrease and/or reverse the symptoms of hypogonadism.

Menopause and andropause differ in several ways, although conceptually they both refer to a decrease in hormones with aging. The decline in serum testosterone is a gradual process, has variable follicle-stimulating-hormone (FSH) and luteinizing-hormone (LH) effects on the pituitary gland, is associated with less-pronounced symptom manifestation, and has no discrete physiological event such as the menstrual termination in women.

Prevalence and Incidence of Hypogonadism

It is estimated that 20% of men 60 to 80 years of age have levels below the lower limit of normal testosterone.³ Approximately 4 million to 5 million men suffer from hypogonadism,⁴ and 95% of these men go untreated (Figure 1). The reason for such a disparity involves unawareness on the part of pharmacists, physicians (the literature on the topic is limited), and patients?men are thus less likely to report symptoms to physicians. A decline in testosterone levels has been shown to be associated with stress, illness, medications (Table 2), obesity, malnutrition, or psychiatric conditions and can lead to future comorbidities among aging men.⁵

Recently, interest and research have been increasing concerning testosterone replacement therapy for men with hypogonadism or related conditions. A recent study has shown that between 1999 and 2002, testosterone prescriptions increased 170%, and between 1998 and 2003, sales of testosterone products increased from $18 million to $400 million.⁶ Because this therapy option is relatively new, large long-term evaluations of the effects of hormone replacement therapy (HRT) on men are limited. The data that have been collected through evaluating organ responses, however, give some insight into the benefits and risks of HRT.⁷

Testosterone Production

Testosterone production in men is controlled by the hypothalamic-pituitary-gonadal axis (Figure 2). Secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the pituitary gland to release LH, which acts on testicular Leydig cells to produce testosterone. Testosterone is metabolized by 5?-reductase to dihydrotestosterone (DHT) and then metabolized to estradiol by aromatase. Increasing concentrations of testosterone inhibit further secretion of GnRH through a negative feedback mechanism. In the pituitary gland, GnRH binds to the GnRH receptor on the gonadotrope surface and stimulates the synthesis and pulsatile secretion of FSH and LH.^8-11 Testosterone is highly bound (60%) to sex-hormone-binding globulin (SHBG) and, to a lesser extent, to other serum proteins, including albumin (38%). Only 2% exists unbound as free testosterone (Figure 3). Bioavailable testosterone refers to non-SHBG-bound forms (including free testosterone) and generally is considered to be the biologically active fraction. As one ages the amount of SHBG increases, which means that more testosterone is bound and not biologically active. This results in lower levels of active testosterone.^12-26

Younger men have a diurnal variation in serum testosterone concentrations, with the highest values seen at 8 AM and the lowest in the late afternoon.²⁷ Elderly men, however, lose this diurnal rhythm. Plasma and urinary androstenediol gluconuride levels (measures of androgen action) also decrease with aging.²⁸ The rate of decrease in total testosterone levels is approximately 110 ng/dL per decade.²⁹ In addition, bioavailable testosterone progressively decreases with aging.³⁰ This decrease is associated with primary gonadal failure and hypothalamic pituitary failure. With age, Leydig cells decrease, steroid hormone biosynthesis and blood supply to the gonads become impaired, and steroid output after administration of human chorionic gonadotropin is decreased.^31-38

Primary and Secondary Causes of Hypogonadism

Many causes of primary (testicular disorder) and secondary (pituitary disorder) hypogonadism are known. Differential diagnosis from a pharmacist's perspective is important (Table 3). The most common causes to recognize are chronic diseases or conditions associated with low testosterone and drug therapy associated with low testosterone. Pharmacists should be aware of medications that may cause secondary hypogonadism (Table 2). Medications such as opiates or anticonvulsants have proven to decrease testosterone levels and affect steroidogenesis and spermatogenesis. Older patients with lung cancer, diabetes, cardiovascular disease, or prostate disease also showed a marked decrease in testosterone levels.³⁹ These decreased testosterone levels can lead to hypogonadism.

Screening for Low Testosterone: A Diagnostic Workup

The initial best screening test for the diagnosis of hypogonadism is an early morning serum total testosterone level. If it is < 300 ng/dL, the patient should be considered hypogonadal. The normal range of total testosterone is 300 to 1050 ng/dL (per current FDA standards). Before labeling the patient as testosterone deficient, however, pathologic causes of hypogonadism should be ruled out. Serum prolactin, thyroid-stimulating hormone, and gonadotropin levels should be measured. If the patient is hypothyroid, L-thyroxine replacement should be started. Low gonadotropin levels indicate central hypogonadism, and an elevated prolactin level may indicate the presence of a pituitary tumor. In both circumstances, magnetic resonance imaging of the pituitary is indicated. If the patient has signs and symptoms of hypogonadism and the total testosterone level is normal, measurement of the free testosterone by equilibrium dialysis should be the next course of action. This occurrence could be in relation to increased sex-hormone-binding globulin levels. An alternative to this test is a measurement of bioavailable testosterone level with ammonium sulfate precipitation.²

Once low testosterone is confirmed, testosterone replacement therapy should be initiated. Before initiation, baseline hematocrit, prostate-specific androgen (PSA) level, and liver enzymes should be measured, and a lipid profile and digital rectal examination should be done. PSA level should be tested 6 months after initiation and annually from then on. Lipid profile, hematocrit, and liver enzymes should be checked every 6 months. Efficacy is determined by assessing clinical response?changes in mood, androgen effects, and sexual effects. Serum testosterone levels are titrated to a midnormal range.²

Clinical Implications of Testosterone Deficiency and Restoration

Most of the information concerning the benefits of testosterone replacement therapy is from animal models and younger patients; however, small trials for older hypogonadal patients suggest therapy safety for up to 3 to 4 years.⁴⁰ Testosterone has been shown to improve body composition and certain domains of brain function, including an increase in libido, well-being, energy, cognitive function, and sleep quality, and a decrease in irritability and depression.

Physical Effects of Testosterone Replacement Therapy

Bone

Testosterone has had beneficial effects on bone in aging males. Osteoporosis in men is an established effect of hypogonadism, and 20% of osteoporosis-related fractures occur in men.² In one study, the risk of hip fractures was about twice as great in elderly men with hypogonadism.²⁸ A study conducted in 1948 showed that older men with osteoporosis had greater calcium retention and decreased bone loss after receiving testosterone replacement therapy.²⁹ A more recent study showed increased bone mineral density in the spine,³³ and other studies also show increased bone formation after therapy.^30-32 Treatment for hypogonadism and its effect on osteoporosis is still controversial and requires more long-term study in order to obtain sufficient data, but the data that have been collected show many beneficial aspects.

Body Composition

The beneficial effects of testosterone replacement therapy on body composition include increased lean body mass, muscle mass and strength, bone mineral density, hair and skin thickness, and physical function, and decreased fat mass, visceral fat, and fractures.¹ The administration of testosterone results in increased synthesis of contractile and noncontractile muscle proteins, increased intramuscular concentrations of mRNA for insulin-like growth factor-1, and decreased abdominal fat mass resulting from lipolysis and decreased lipid uptake into the abdominal fat depot.² Muscle strength and quantity are directly related with lower testosterone levels occurring as men age and often result in weakness of limb-girdle muscles.³⁸

Cardiovascular

Studies suggest a decrease in cardiovascular risk in response to testosterone replacement therapy and beneficial effects on insulin resistance and hypertension, and in reducing waist-to-hip ratio.⁴¹ Improved coronary blood flow and increased coronary artery diameter after testosterone administration were also benefits for cardiac status. However, some men with hypogonadism receiving testosterone replacement therapy developed polycythemia (increased blood viscosity). This condition adds to poor cardiovascular health and has serious consequences in elderly patients.

Despite the mixed effects of testosterone replacement therapy on the cardiovascular system, researchers did not find increases in angina pectoris, myocardial infarction, or stroke over a 3-year period with testosterone replacement therapy.^42-44

Sexual Effects

Testosterone is necessary for libido, erectile function, and normal ejaculation.^45-47 Lower testosterone levels due to aging are often associated with a decrease in erectile function and frequency of orgasm, and an increase in refractory period.⁴⁸ Other sexual effects associated with aging include a decrease in vasocongestive responses, sexual thoughts, and enjoyment. Testosterone replacement therapy has shown many improvements in sexual function for older men. The most common result of oral or transdermal treatment is an increase in penile rigidity and number of erectile events per hour as well as improved sexual performance.³⁴ In a study of men with erectile dysfunction, testosterone replacement therapy resulted in increased frequency of ejaculation and masturbation, sexual desire, and sleep-related erections.³⁵

Emotional Effects

Testosterone is directly related to many emotional aspects of men's lives. Depression, sense of well-being, anxiety, concentration, and memory are all affected by testosterone. Low levels of testosterone can have serious effects on these emotional aspects, and studies of testosterone replacement therapy have shown beneficial evidence for helping to decrease the severity of these symptoms.^5,36,49

Therapy in older men has been shown to increase the sense of well-being and enhance spatial cognition,⁴⁹ and in some patients it had an antidepressant effect.^5,36 In addition, a recent study showed that testosterone reduces neuronal secretion of beta amyloid peptide, the major protein in the plaques associated with Alzheimer's disease.³⁷

Safety Issues in Testosterone Replacement

Testosterone replacement therapy is associated with adverse effects that include acne, erythrocytosis, suppression of sperm production, gynecomastia, fluid retention, edema, and local reactions to injections and patches, and a worsening of sleep apnea, increase in lean body mass, and weight gain.^4,39,40 Gynecomastia is due to estradiol, which is converted from testosterone and can be minimized by flavones and zinc.

Serious medical conditions can be associated with administration of testosterone to men with hypogonadism. Testosterone replacement has been shown to increase low-density lipoprotein cholesterol levels and triglycerides, decrease high-density lipoprotein cholesterol levels, and induce insulin resistance and carbohydrate intolerance. Coronary artery disease in older men correlated with lower testosterone levels more so than those with reduced coronary artery narrowing. Men with type 2 diabetes also showed evidence of lower androgen levels and dyslipidemia. Testosterone does not have serious adverse effects on cardiac status or coagulation of blood.

The prostate gland can be adversely affected by testosterone replacement. Prostate cancer and benign prostatic hypertrophy (BPH) rates increase as men age and testosterone levels decrease. Although the evidence that testosterone replacement causes a higher risk of prostate cancer is not definitive, treatment with testosterone replacement therapy is contraindicated in men with known prostate cancer. A recent study demonstrated that one of the metabolites of testosterone, DHT, has a greater stimulatory effect on the prostate than testosterone.⁵⁰ Testosterone is converted to DHT by 5-?-reductase, an enzyme found in the skin as well as in male reproductive tissues, the prostate, and the liver.⁵⁰ In addition, administered testosterone may cause breast cancer in men when the testosterone is converted to estrogen estradiol.⁵

Testosterone Treatment

Patients with hypogonadotropic hypogonadism should receive therapy directed toward the underlying pituitary hypothalamic disorder.¹⁸ Testosterone delivery options include oral preparations, skin patch, gel, subcutaneous implants, intramuscular injections, and buccal formulations.

Buccal System

The buccal form is a relatively new testosterone delivery system. Recent pharmacokinetic studies show that it closely approximates the restoration of normal physiological testosterone levels.^51,52 Other advantages of this method include pharmacokinetic and physiologically consistent therapeutic levels of testosterone without the need for repeated titrations. Therapy with the buccal system results in low DHT conversion and no risk of transference to female partners or children. Drawbacks include twice-daily dosing and some initial gum irritation in some (9%) patients.

The recommended dosing schedule is the application of 1 buccal system (30 mg) to the gum region just above the incisor tooth twice daily, in the morning and evening (about 12 hours apart). With each application, the product should be rotated to the alternate side of the mouth. Patients should be instructed to place the side with the rounded surface against the gum and to hold it firmly in place with a finger over the lip for 30 seconds to ensure adhesion. The preparation does not dissolve completely and must be removed before placing a new buccal system on the alternate side of the mouth. The buccal testosterone delivery system is not affected by eating, tooth brushing, gum chewing, or alcoholic beverages. It is important to also explain that the preparation should never be chewed or swallowed. Long-term clinical data safety are limited, but preliminary data show good patient acceptance and tolerability.^53,54

Transdermal Testosterone Patch

The transdermal patch is a convenient-to-use noninvasive therapy, and it closely mimics normal diurnal changes in testosterone in normal men. Drawbacks include skin irritation and problems with the patch adhering properly, especially in hot climates. Transdermal patches are applied at the same time of day, typically every evening between 8:00 PM and midnight. Patients should be instructed to place the patch on a clean dry area on the back, abdomen, thighs, or upper arms but never on genitals or damaged skin. To reduce the likelihood of skin irritation, subsequent patches should not be placed in the same spot for at least 1 week. The patient can maintain most forms of normal activity, such as sex, swimming, and showering. If excessive perspiration or moisture causes the patch to loosen or fall off, it can be pressed back down or replaced if this occurs before noon.⁵⁵ Dose may be titrated from 2.5 mg/day to 7.5 mg/day based on morning testosterone levels.

Transdermal Gel

Testosterone gel provides therapeutic testosterone levels without large fluctuations, and it is easier to use and causes less skin irritation than patches. Disadvantages include risk of DHT conversion, skin irritation, and the risk of transference to female partners and children. In addition, the patient should be told not to swim or shower for 5 to 6 hours after application. Instruct patients to apply testosterone gel at a starting dose of 5 g (to deliver 50 mg of testosterone) once daily (preferably in the morning) to clean, dry, intact skin of the shoulders and upper arms and/or abdomen. After opening the packet, the entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternatively, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply it to the application sites. Repeat this process until the entire contents have been applied. Application sites should be allowed to dry for a few minutes prior to dressing so that the testosterone does not rub off onto the clothing. Dose titration may be required and can be increased to 10 g. Hands should be washed with soap and water after the gel has been applied to avoid transference to others.^{55, 56}

Implant Pellets

Although uncommon in the United States, surgically implanted pellets are a long-acting and convenient testosterone delivery system. Disadvantages include potential fluctuations in testosterone levels, inflammation and pain at pellet site, difficulty adjusting dose, pellet extrusion (8% to 10% of patients), and the invasive nature of the surgical procedure. The standard dose is 4 to 5 200-mg pellets every 4 to 6 months.⁸

Oral Testosterone Preparations

Oral preparations have lost patient and medical-community acceptance as an effective testosterone delivery system due to several limitations. Disadvantages include poor oral bioavailability requiring multiple dosing, poor androgen effect, adverse lipid changes, priapism, and higher rate of hepatic side effects (elevated liver function tests, hemorrhagic liver cyst, cholestasis, hepatocellular cancer) due to increased dosing.

Long-Acting Injectables

Long-acting injectable testosterone delivery systems are safe, but disadvantages include frequent (every 2 to 4 weeks) intramuscular injections and significant fluctuations in testosterone levels from high to low over the dosing period. Longer intervals (4 weeks and greater) can result in even greater fluctuations in testosterone levels, which can lead to variations in libido, sexual function, energy, and mood. The recommended initial dose is 100 mg to 150 mg every 2 weeks. Thereafter, it is administrated in doses of 50 mg to 400 mg every 2 to 4 weeks.

Monitoring Patients on Testosterone Replacement

Baseline testing of patients on testosterone replacement includes hemoglobin and hematocrit levels (to detect polycythemia), liver function tests, PSA, digital rectal exam, lipid panel, and morning free- and total-testosterone levels. These laboratory tests should be repeated periodically, usually every 3 to 6 months. The goal of testosterone replacement is to achieve a resolution of the symptoms of hypogonadism and achieve testosterone levels in the normal range. It is important to test testosterone levels in the morning, due to diurnal fluctuations in testosterone production. Testosterone replacement therapy should be stopped if a significant increase in PSA level occurs or a rectal exam is abnormal.²⁰

Natural Products

Many herbal medications are being used for symptoms of hypogonadism. These include human growth hormone, dihydroepiandrosterone (DHEA), melatonin, ginkgo biloba, saw palmetto, St. John's wort (an inducer of cytochrome P450 34A), garlic, and vitamin E.

DHEA is a substance closely related chemically to testosterone and actually breaks down in the body to become testosterone. DHEA is involved in several functions, including immune system support, tissue maintenance and repair, and mental support. Like testosterone, DHEA peaks at the time of puberty and early adulthood, and then declines with age. DHEA is manufactured in the body by the adrenal glands and cannot be found in any food substance. Most of the commercial DHEA is made synthetically. Data suggest that DHEA may be involved in drug interactions with the cytochrome P450 system. Specifically, DHEA is an inhibitor of cytochrome P450 34A. Since testosterone is metabolized by this same system, serum levels can be negatively affected if used with DHEA. More studies are required in this area of naturopathic medicine.⁵⁷

Summary

Low testosterone hypogonadism and the concept of andropause are exciting and growing areas of study in medicine. Although controversy exists over the exact amount of testosterone required and the frequency with which the medication should be administered, data are growing that testosterone replacement can have meaningful impact on the patient's quality of life. Pharmacists are at the forefront of patient access, so it is important to understand the medications available and to counsel appropriately on drug therapies used in this common yet underrecognized condition. Pharmacists will increasingly play a pivotal role in counseling patients receiving new testosterone delivery systems such as the transdermal patch, gel, and the novel buccal testosterone system. Additional long-term studies are required to establish the utility of drug therapy in the patient, but the search for quality of life, youthful vigor, and energy continue to be a journey for mankind.

Narinder Duggal, BSc (Pharm), CGP, BCPP, MD, FRCPC, FASCP: Clinical Associate Professor, School of Pharmacy?University of Washington, Seattle, WA Medical Director, Liberty Bay Internal Medicine

For a list of references and suggested reading, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.

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CE REVIEW QUESTIONS

(Based on the article starting on page 50.) Choose the 1 most correct answer.

1. What is the average life expectancy of a man in America today?

• 65 years old
• 75 years old
• 85 years old
• 60 years old

2. All of the following are synonyms of andropause EXCEPT:

• Androgen deficiency in the aging male (ADAM)
• Aging-associated androgen deficiency (AAAD)
• Partial androgen deficiency in the aging male (PADAM)
• Metabolic syndrome

3. Which of the following is a sign of low-testosterone state?

• Decrease in body hair
• Increase in muscle mass
• Increase in bone density
• Increase in hematopoiesis

4. In andropause and menopause, there is a gradual onset of symptoms.

• True
• False

5. What percentage of men aged 60 to 80 years have andropausal symptoms?

• 20%
• 30%
• 50%
• 80%

6. Pathophysiologic decrease in testosterone at the testicles (primary hypogonadism) results in increasing follicle-stimulating-hormone (FSH) and luteinizing-hormone (LH) levels.

• True
• False

7. In the pituitary gland, gonadotropin-releasing hormone (GnRH) binds to the GnRH receptor on the gonadotrope surface and stimulates the synthesis and pulsatile secretion of FSH and LH.

• True
• False

8. Testosterone is a highly protein-bound sex hormone. As one ages, the sex-hormone-binding globulin will increase. Free testosterone levels (biologically active) will thus:

• Increase
• Stay the same
• Decrease
• None of the above

9. Diurnal variation in testosterone levels would indicate that the best time to draw a testosterone level is:

• Evening
• Noon
• Morning
• Time has no effect

10. All of the following medications can affect testosterone level EXCEPT:

• Ketoconazole
• Phenytoin
• Opioids
• Lovastatin

11. If a patient is experiencing hypogonadal symptoms but has normal testosterone levels, what course of action should be taken?

• Measure free-testosterone levels
• Measure gonadotropin levels
• Conduct magnetic resonance imaging of the pituitary gland
• Initiate testosterone replacement therapy

12. Testosterone replacement therapy has been associated with a decreased sense of well-being.

• True
• False

13. What percentage of osteoporosis-related fractures occur in men?

• 10%
• 20%
• 50%
• 70%

14. Beneficial aspects of testosterone on body composition include:

• Synthesis of contractile and noncontractile muscle proteins
• Increased intramuscular concentrations of mRNA
• Decreased lipid uptake into the abdominal fat depot
• All of the above

15. Studies of testosterone replacement therapy and cardiovascular events have shown:

• An increase in stroke and myocardial infarction
• Decreased coronary blood flow and coronary artery diameter
• A development of polycythemia in some patients
• Harmful effects on insulin resistance and hypertension

16. Overall beneficial aspects of testosterone replacement therapy include:

• Increased sleep quality
• Increased muscle mass and strength
• Increased body hair and skin thickness
• All of the above

17. Testosterone replacement therapy is directly related to prostate problems.

• True
• False

18. Which of the following is NOT a potential risk of testosterone replacement therapy?

• Urinary incontinence
• Weight gain
• Fluid retention
• Gynecomastia

19. Which of the following is NOT a unique property of the buccal testosterone system?

• Mimics pharmacokinetic and physiological testosterone levels
• Has low dihydrotestosterone conversion
• Has high transference from patient to patient
• Is not affected by food, tooth brushing, gum chewing, or alcohol beverages

20. What is the recommended initial dose of long-acting injectable testosterone?

• 10-20 mg every 2 weeks
• 5-20 mg every 2 weeks
• 30-50 mg every 2 weeks
• 100-150 mg every 2 weeks