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Testosterone Deficiency
Overview
Testosterone production declines naturally with age. Testosterone deficiency (TD) may result from disease or damage to the hypothalamus, pituitary gland, or testicles that inhibits hormone secretion and testosterone production, and is also known as hypogonadism. Depending on age, insufficient testosterone production can lead to abnormalities in muscle and bone development, underdeveloped genitalia, and diminished virility.
Testosterone is the androgenic hormone primarily responsible for normal growth and development of male sex and reproductive organs, including the penis, testicles, scrotum, prostate, and seminal vesicles. It facilitates the development of secondary male sex characteristics such as musculature, bone mass, fat distribution, hair patterns, laryngeal enlargement, and vocal chord thickening. Additionally, normal testosterone levels maintain energy level, healthy mood, fertility, and sexual desire.
The testes produce testosterone regulated by a complex chain of signals that begins in the brain. This chain is called the hypothalamic-pituitary-gonadal axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) to the pituitary gland in carefully timed pulses (bursts), which triggers the secretion of leutenizing hormone (LH) from the pituitary gland. Leutenizing hormone stimulates the Leydig cells of the testes to produce testosterone. Normally, the testes produce 4–7 milligrams (mg) of testosterone daily.
Incidence and Prevalence
Testosterone production increases rapidly at the onset of puberty and decreases rapidly after age 50 (to 20% to 50% of peak level by age 80). Approximately 8 million men in the United States experience testosterone deficiency; approximately 600,000 receive treatment.
Types and Causes
Testosterone deficiency (hypogonadism) may be present at birth (congenital) or may develop later (acquired). It is classified by the location of its cause along the hypothalamic-pituitary-gonadal axis:
• Primary, disruption in the testicles
• Secondary, disruption in the pituitary
• Tertiary, disruption in the hypothalamus
The most common congenital cause is Klinefelter's syndrome. This condition, which is caused by an extra X chromosome, results in infertility, sparse facial and body hair, abnormal breast enlargement (gynecomastia), and small testes.
Congenital hormonal disorders such as leutenizing hormone-releasing hormone (LHRH) deficiency and gonadotropin-releasing hormone (GnRH) deficiency (e.g., Kallmann's syndrome) also may cause testosterone deficiency.
Other congenital causes include absence of the testes (anorchism; also may be acquired) and failure of the testicles to descend into the scrotum (cryptorchidism).
Acquired causes of testosterone deficiency include the following:
• Chemotherapy
• Damage occurring during surgery involving the pituitary gland, hypothalamus, or testes
• Glandular malformation
• Head trauma that affects the hypothalamus
• Infection (e.g., meningitis, syphilis, mumps)
• Isolated LH deficiency (e.g., fertile eunuch syndrome)
• Radiation
• Testicular trauma
• Tumors of the pituitary gland, hypothalamus, or testicles
Signs and Symptoms
Signs depend on the age of onset and the duration of hormonal deficiency. Congenital testosterone deficiency is generally characterized by underdeveloped genitalia (testes that do not descend into the scrotum) and, occasionally, undeterminable genitalia. Acquired testosterone deficiency that develops near puberty can result in enlargement of breast tissue (gynecomastia), sparse or absent pubic and body hair, and underdeveloped penis, testes, and muscle. Adult men may experience diminished libido, erectile dysfunction, muscle weakness, loss of body hair, depression, and other mood disorders.
Complications
Testosterone deficiency has been linked to muscle weakness and osteoporosis. In one study, proximal and distal muscle weakness was detected in 68% of men with primary or secondary hypogonadism. Spinal, trabecular, and radial cortical bone density may also be significantly reduced in testosterone-deficient men. Thirty percent of men with spinal osteoporosis have long-standing testosterone deficiency, and one-third of men have subnormal bone density that puts them at risk for fracture.
Diagnosis
Serum and blood testing is done to determine the availability of testosterone and levels of leutenizing and gonadotropin-releasing hormones in the body. Men with low testosterone in whom normal or high gonadotropin levels are found typically have primary testosterone deficiency, which stems from a problem in the testicles. Secondary and tertiary types, caused by problems of the hypothalamus or pituitary gland, often result in low testosterone and low gonadotropin levels.
Other tests involve injecting GnRH or clomiphene citrate (an estrogen) to stimulate a diagnostic response within the hypothalamic-pituitary gonadal axis.
Rarely, testicular biopsy is done, usually in cases where sperm is absent from ejaculate despite normal testicle development. Biopsy, which involves using a needle to collect a sample of testicular tissue, may detect a malfunction in sperm production.
Treatment
Treatment involves hormone replacement therapy. The method of delivery is determined by age and duration of deficiency. Oral testosterone (methyltestosterone, Testred®) is associated with liver toxicity and liver tumors and so is prescribed sparingly.
Treatment for adults is aimed at maintaining secondary sex characteristics, improving energy, strength, mood, and feelings of well-being, and preventing bone degeneration. Modes of delivery include transdermal, mucoadhesive, and intramuscular injection.
Transdermal delivery (i.e., through the skin) with a testosterone patch is becoming the most common method of treatment for testosterone deficiency in adults. It establishes and maintains adequate serum levels in as many as 92% of men treated, without causing significant side effects.
A patch is worn, either on the scrotum or elsewhere on the body, and testosterone is released through the skin at controlled intervals. Patches are typically worn for 12 or 24 hours and can be worn during exercise, bathing, and strenuous activity. Two transdermal patches that are available are Androderm® (nonscrotal) and Testoderm® (scrotal).
The Androderm® patch is applied to the abdomen, lower back, thigh, or upper arm and should be applied at the same time every evening between 8PM and midnight. If the patch falls off before noon, replace it with a fresh patch until it is time to reapply a new patch that evening. If the patch falls off after noon, do not replace it until you reapply a new patch that evening.
The most common side effects associated with transdermal patch therapy include itching, discomfort, and irritation at the site of application. Some men may experience fluid retention, acne, and temporary abnormal breast development (gynecosmastia).
Androgel®/Testim™ are transdermal gels that are applied once daily to the clean dry skin of the upper arms or abdomen. Gels deliver testosterone for 24 hours when used properly. The gel must be allowed to dry on the skin before dressing and must be applied at least 6 hours before showering or swimming. Gels cannot be applied to the genitals. Side effects may include adverse reaction at the site of application, acne, headache, and hair loss (alopecia).
Mucoadhesive delivery allows testosterone to enter the bloodstream directly, bypassing the gastrointestinal tract and the liver.
Striant™ (testosterone buccal system) mucoadhesive CIII is a hormone-replacement treatment that delivers testosterone twice daily through a tablet-like buccal system that adheres to the gum or cheek. It is placed in the mouth where the gum meets the upper lip and dissolves into a gel that remains in place for 12 hours. As the product absorbs moisture, it gradually releases testosterone directly into the bloodstream, bypassing the gastrointestinal tract and the liver. In clinical trials, approximately 87% of patients obtained normal testosterone levels using Striant™.
Side effects are usually mild and transient (i.e., come and go) and resolve within 2 weeks. They include gum or mouth irritation, pain, and swelling (edema); bitter taste, and headache. Abnormal breast development (gynecomastia) may also occur. Patients should report persistent gum abnormalities to their physician.
Striant™ should not be used in men with prostate or breast cancer and should be used with caution in patients with chronic heart, kidney, liver, or lung disease. It may cause edema, congestive heart failure, and sleep apnea, and may increase the risk for enlarged prostate and prostate cancer. Patients taking the medication must undergo regular digital rectal examinations (DRE) and prostate-specific antigen (PSA) tests to monitor for signs of the disease. For complete patient and safety information click here.
Intramuscular injection (IM) is used less frequently because it is associated with erratic testosterone levels. The primary adverse effect associated with injected testosterone involves fluctuating mood, energy level, and libido caused by testosterone levels that rise rapidly upon injection and then fall too low before the next dose.
Kallmann's syndrome may be treated with chorionic gonadotropin, which can correct undescended testicles (cryptorchidism) and infertility. Gonoadotropin releasing hormone (GnRH) therapy can trigger secretion of testosterone and other sex steroids, initiate virilization, and may establish fertility.
Children and adolescents with low testosterone and delayed puberty may be treated with low doses of testosterone through intramuscular injection to induce puberty. Adolescents may receive gradually increasing doses that last longer in the body, because, with age, there is less risk for affecting normal growth patterns.
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