Testosterone Replacement Therapy

Introduction

Testosterone is responsible for normal growth and development of male sex organs and maintenance of secondary sex characteristics. It is the primary androgenic hormone, and its production and secretion are the end product of a series of hormonal interactions. Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus and controls the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary. Luteinizing hormone regulates the production and secretion of testosterone by the Leydig cells of the testes, and FSH stimulates spermatogenesis.

When the testes fail to produce normal levels of testosterone, testosterone deficiency results. Hypergonadotropic hypogonadism is caused by primary testicular failure. Testosterone levels are low and pituitary gonadotropins are elevated. In secondary, or hypogonadotropic hypogonadism, there is inadequate secretion of pituitary gonadotropins. In addition to a low testosterone level, LH and FSH levels are low or low-normal.1, 2 While pre-pubertal hypogonadism is generally characterized by infantile genitalia and lack of virilization, the development of hypogonadism after puberty frequently results in complaints such as diminished libido, erectile dysfunction, infertility, gynecomastia, impaired masculinization, changes in body composition, reductions in body and facial hair, and osteoporosis.1 In addition to these complaints, mood inventory scores indicate that hypogonadal men report levels of anger, confusion, depression, and fatigue that are significantly higher than those reported by men with normal testosterone levels.3

Men with primary hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism are candidates for testosterone replacement therapy, and there are now a variety of products available to treat these disorders. Successful management of testosterone replacement therapy requires appropriate evaluation and an understanding of the benefits and risks of treatment.

Diagnosis of Testosterone Deficiency

Given the variety of causes of testosterone deficiency, a medical and medication history, physical exam, and directed laboratory evaluation are imperative. The medical history should include questions regarding developmental abnormalities at birth, the rate and extent of virilization at the time of puberty, and the current status of sexual function and secondary sexual characteristics, such as beard growth, muscular strength, and energy level. Hypogonadal men have statistically significant reductions in the incidence of nocturnal erections, the degree of penile rigidity during erection, and the frequency of sexual thoughts, feelings of desire, and sexual fantasies.3 Alterations in body composition, including increases in percent body fat, changes in adipose tissue distribution, and reduction in muscle mass, are frequently seen in hypogonadal men.4,5 Spinal trabecular bone density is also decreased in men with hypogonadotropic hypogonadism,6 and hip fractures are more common in hypogonadal men than in normal men.7

Initially, hormonal screening is limited to measurement of total serum testosterone, which is obtained in the morning. When the total testosterone level is low and/or the patient complains of reduced libido, a serum prolactin level should also be measured. A high serum prolactin level may indicate pituitary dysfunction and may require consultation with an endocrinologist. Serum LH levels are measured when serum prolactin levels are normal or low to help differentiate intrinsic testicular failure from a pituitary or hypothalamic abnormality. LH is usually high in patients with primary testicular disease. When the serum testosterone level is low and LH is elevated, testosterone replacement therapy is warranted.

Testosterone Replacement Therapy

Testosterone replacement should in theory approximate the natural, endogenous production of the hormone. The average male produces 4-7 mg of testosterone per day in a circadian pattern, with maximal plasma levels attained in early morning and minimal levels in the evening.8 However, the subtleties of pulsatile and diurnal rhythms are potentially difficult to imitate, and evidence suggests that different dose response curves exist for different androgen-dependent functions.9 The clinical rationale for treatment of testosterone deficiency may include:
-stabilizing or increasing bone density
-enhancing body composition by increasing muscle strength and reducing adipose
-improving energy and mood
-maintaining or restoring secondary sexual characteristics, libido and erectile function

Types of Testosterone Replacement Therapy

Ideal testosterone replacement therapy produces and maintains physiologic serum concentrations of the hormone and its active metabolites without significant side effects or safety concerns. Several different types of testosterone replacement are currently marketed, including tablets, injectables, and transdermal systems.

Oral agents

Although elevations in liver function tests and abnormalities at liver scan and biopsy are relatively common in patients receiving oral testosterone,10 these preparations still constitute roughly a third of the testosterone prescriptions filled in the United States. Both modified and unmodified oral testosterone preparations are available. Unmodified testosterone is rapidly absorbed by the liver, making satisfactory serum concentrations difficult to achieve. Modified 17-alpha alkyltestosterones, such as methyltestosterone or fluoxymesterone, also require relatively large doses that must be taken several times a day.

Intramuscular injection

Testosterone cypionate and enanthate are frequently used parenteral preparations that provide a safe means of hormone replacement in hypogonadal men. Testosterone is esterified to inhibit degradation and to make it soluble in oil-based injection vehicles that retain the drug in muscle tissue. In men 20-50 years of age, an intramuscular injection of 200 to 300 mg testosterone enanthate is generally sufficient to produce serum testosterone levels that are supranormal initially and fall into the normal ranges over the next 14 days. Fluctuations in testosterone levels may yield variations in libido, sexual function, energy, and mood. Some patients may be inconvenienced by the need for frequent testosterone injections.11 Increasing the dose to 300 to 400 mg may allow for maintenance of eugonadal levels of serum testosterone for up to three weeks, but higher doses will not lengthen the eugonadal period.12

Transdermal systems

Currently, three testosterone transdermal systems are marketed: a system applied to the scrotum that has no permeation enhancers [Testoderm, 6 mg, ALZA Corporation, Palo Alto, CA] and two systems that contain permeation enhancers for application to appendage or torso skin [Androderm 2.5 mg and 5 mg, SmithKline Beecham Pharmaceuticals, Philadelphia, PA; Testoderm TTS, 5 mg, ALZA Corporation, Palo Alto, CA]. Scrotal patches produce high levels of circulating dihydrotestosterone (DHT) due to the high 5-alpha-reductase enzyme activity of scrotal skin.

Clinical studies of transdermal systems demonstrate their efficacy in providing adequate testosterone replacement therapy.13-15 Skin irritation may be associated with the use of transdermal systems; however, Testoderm and Testoderm TTS caused significantly less topical skin irritation than Androderm in two separate clinical studies.16,17

Monitoring Patients on Testosterone Replacement

Patients on testosterone replacement therapy should be monitored to ensure that testosterone levels are within normal levels. The physician prescribing testosterone replacement should evaluate any changes in the clinical symptoms and signs of testosterone deficiency and should assess for other concerns, such as acne and increase in breast size and tenderness. Serum testosterone levels should be checked three to 12 hours after application of a transdermal delivery system. For patients on injectable testosterone, nadir testosterone levels should normally be obtained at three to four months prior to the next injection. Levels that exceed 500 ng/dL or are less than 200 ng/dL require adjustment of the dose or frequency.

A digital rectal examination (DRE) should be performed and prostate specific antigen (PSA) checked in all men before initiating treatment. These should be repeated at approximately three to six months, and then annually in men >40 years of age. An abnormal DRE, a confirmed increase in PSA >2 ng/mL, or a total PSA >4.0 ng/mL requires urologic evaluation that usually consists of transrectal ultrasonography and sextant prostate biopsies. The hematocrit level should also be checked at baseline, at three to six months, and then annually. A hematocrit >55% warrants evaluation for hypoxia and sleep apnea and/or a reduction in the dose of testosterone therapy. Measurement of bone mineral density of the lumbar spine and/or the femoral necks at one year may be considered in hypogonadal men with osteopenia.

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