Synthetic (man-made) testosterones represent the typical drugs used to treat low testosterone, a condition that often causes a variety of adverse hypogonadic symptoms. Belonging to a class of medications called anabolic steroids, synthetic testosterone supports deficient endogenous (natural) testosterone levels by either elevating the total hormone levels back into the normal range, or raising these levels high enough within the normal range to reverse negative hypogonadic symptoms. There are different variations (esters, delivery mechanisms, blends, etc.) of synthetic testosterone each with its own unique properties, and respective methods of action.

Hypogonadic Symptoms of Low Testosterone

Testosterone is a naturally occurring male sex hormone that is vital to the development of males throughout the lifespan, from prenatal development onward. Later in life, the hormone testosterone is responsible for numerous very important physiological processes, which will become evident during the exploration of hypogonadic (low testosterone) symptoms. Regardless of the specific causes or reasons for low testosterone, i.e., primary, secondary, or tertiary hypogonadism the symptoms are largely the same. Although said symptoms are numerous, and varied with regard to severity, they are most commonly characterized by the following:

• Changes in mood, which can manifest as irritability, depression, anger and fatigue
• Decreased libido (sexual desire), and diminished erectile quality and overall sexual performance
• Diminished capacity to burn body fat, resulting in more visceral (between and surrounding internal organs) and/or subcutaneous (below the skin) fat
• Decreased bone density, which increases the risk for breaks, fractures, and osteoporosis
• Reduction in lean body mass, and overall muscular strength
• Changes in cholesterol and lipid values
• Decreased body hair (both amount and thickness)
• Depressed or below normal hemoglobin levels, and possibly mild anemia
• Reduced energy levels, and lessened interest and participation in usual activities
• Complications getting to and staying asleep throughout the night
• Problems with mental faculties such as loss of memory, trouble recalling facts or events, lack of mental clarity (concentration, focus, attention, etc.)
• General malaise – a condition most characterized as general bodily weakness or discomfort, often marking the onset of a disease; a vague or unfocused feeling of mental uneasiness, lethargy, or discomfort

Forms of Testosterone Used in Treatment

There are a variety of available Testosterone Replacement Therapy (TRT) medication forms, or options for those with low testosterone levels to choose from. The basic treatment is any one of numerous synthetic testosterone preparations, and although each provides adequate levels of hormone replacement, each also possesses unique properties. Although they are not inherently positive or negative characteristics, they can be perceived as so with regard to the user’s specific lifestyle or needs. For example, orals require daily administration, which may be problematic for fast paced individuals with busy lives. Similarly, Nebido is an infrequently administered extremely long-term treatment, which isn’t appropriate for female patients who may experience hazardous side effects that require quick reversal. The selection of a specific testosterone preparation depends on multiple factors including cost, convenience of use, swiftness of reversibility should a grossly adverse side effect occur, frequent or infrequent administration, etc. It is therefore incumbent upon the patient and physician to communicate both prior to and after TRT has begun with regard to the testosterone preparation that best suits a specific lifestyle.

INJECTIONABLE SOLUTIONS

Chemically speaking, testosterone is a singular hormone, which in the case of injectable solutions consists of added esters. An ester is an addition that primarily changes the rate (or speed) of the medication’s absorption. The amount of testosterone released into the bloodstream is controlled over time, very much like that of a time-released multivitamin. Esters can be invaluable as they permit longer periods between injections.

Intramuscular (IM) testosterone injections constitute a very popular form of testosterone preparation. IMs are shot directly into the muscle, and then absorbed into the bloodstream via the capillaries. They are not only popular because of their varying time release qualities, but also because they don’t cause significant hepatotoxicity or hinder liver functioning. The four primary U.S. approved injectable testosterone preparations for TRT include:

1. Testosterone propionate, a short, fast-acting (2-3 days) ester
2. Testosterone cypionate, a medium, longer-acting (7-8 days) ester
3. Testosterone enanthate, a long-acting (7-8 days) ester
4. Nebido, the very long-acting 2009 FDA approved testosterone undecanoate that actually permits medicinal dosing four times per year, i.e. every 3 months/90 days

Other injectable preparations include hybrid combinations of fast, moderate, and slow release esters most notably Sustanon 250, and its lesser known hybrid relative Omnadren 250. Hybrid preparations provide the best of both worlds, working quickly and providing longer lasting effects. Short esters like propionate, and the even faster no ester testosterone version known as suspension (not FDA approved for testosterone replacement therapy), work very quickly (within a couple of days), but also stop working almost immediately following discontinuation, i.e. within about a week’s time. Such esters require more frequent injections and greater injection site rotation. Medium and longer esters work inversely, taking longer to accumulate within the bloodstream and begin working, and longer to evacuate the body via the three processes of absorption, degradation, and elimination.

ORALS

Oral tablets will always be popular because of their unique vitamin-like convenience, and ease of use. Many men prefer this form, not only because they’re already accustomed to taking vitamins, but also due to their disenchantment with needles. However, tablets are harsher on the liver than other preparations, and are generally taken daily or twice daily to guarantee that proper blood serum levels are maintained throughout the day and night. However, this same frequent dosing requirement can make tablet taking easy to forget, especially for those men who are unaccustomed to a daily vitamin regimen. Significant clinical trials evaluating oral testosterone therapies date back approximately 20 years as oral preparations offer:

• Greater privacy
• Vitamin-like convenience and ease of use
• A viable option to needles for the injection squeamish
• The confidence of rapid and effective testosterone replacement

Conversely, orals can produce specific negative side effects like hepatotoxicity, a.k.a. liver toxicity in which the liver and cholesterol values become negatively skewed, by virtue of the digestive process. Paradoxically, some oral users actually experience diminished libido, even though TRT is supposed to improve sexual problems. Although often taken once daily, due to their short half-lives orals are most effective when administered twice daily to ensure adequately steady blood serum concentrations.

TRANSDERMALS

Transdermals are another viable testosterone delivery method, the most popular of which include patches and gels. Transdermals combine many of the characteristics from other applications. For example, they require more frequent (daily) administration similar to tablets, and elevate serum levels and reach peak serum concentrations quickly like short ester intramuscular testosterone propionate. Applied to and absorbed through the skin, transdermals are then absorbed by the capillaries directly into the bloodstream, and much like intramuscular injections they do not promote significant hepatotoxicity.

The patch comes in a variety of dosages and brands, the most prescribed of which is Androderm. Patch application require daily (every 24 hours) changing which, like taking orals, can be problem for some patients. Older versions of the testosterone patch required attachment to the scrotum, but today’s patches may be applied to any clean, dry, muscle dense area wherein special preference is given to the upper arms, thighs, stomach, and back. To provide for optimal absorption, it is important to rotate attachment sites daily thereby allowing at least seven days to elapse prior to reusing a site. Androderm produces serum testosterone levels that mimic normal circadian changes, and are equivalent to the normal midrange for young adult men. A somewhat pliable preparation, the Androderm patch affords a measure of dosing flexibility, as it is available in two sizes (2.5 mg and 5 mg). Although reportedly uncomfortable for some patients, after a short acclimation period most users don’t even realize they have it on. Some patients experience allergic reactions to the adhesive in testosterone patches, which can manifest in a variety of skin irritations.

The other widely used and available transdermal preparation is the testosterone gel. The very popular AndroGel, manufactured by Unimed Pharmaceuticals Inc., boasts solid delivery reliability, and the same application principles adhered to with the patch apply to gel preparations as well. More specifically, the gel should be applied to a clean, dry, muscle dense bodily region, preferably the upper arms, thighs, stomach, and back. Similarly, it is important to rotate application sites daily, and to permit at least seven days to pass before reusing a site in order to promote optimal testosterone absorption. Recently, another transdermal testosterone gel called Testim (from Auxilium Pharmaceuticals) received FDA approval for TRT use within the United States. The testosterone serum levels obtainable with Testim administration appear to be quite similar to those obtained with AndroGel.

PELLET IMPLANTS

Testopel is a subcutaneous crystalline testosterone pellet manufactured by Organon, and approved in the U.S. for the treatment of men with testosterone deficiency syndrome (low testosterone). This long-acting pellet is inserted subcutaneously (between skin layers), and can provide a sustained testosterone release for 3 to 6 months. For obvious reasons, such a method is not as popular as some of the other preparations mentioned above, but these pellets are still just as effective.

First developed in the 1940s, testosterone pellets are a very old form of TRT. Each pellet contains 75 mg of crystalline testosterone designed to provide slow release for up to six months in duration. Contingent upon the required dosage, 2 to 6 pellets are implanted beneath the skin typically in the glutes, upper thighs, lower abdomen, or deltoid every 3 to 6 months. Similar to orals, transdermals, and short ester injectable solutions, pellets provide rapid peak physiologic testosterone levels. However, more akin to very long ester injectable solutions, pellet dosages and benefits decline gradually over a 6-month period, which substantially minimizes side effects. Not often used within the United States, pellet implantation is surgical, can be painful, and pellets have a tendency to extrude (be pushed out by pressure over time). Their very long duration of action makes reversibility difficult, and also makes pellets largely unsuitable for use in populations for whom adverse side effects are more common, such as women and elderly patients.

TRANSBUCCAL (BUCCAL) SYSTEM

Transbuccal testosterone, a.k.a. buccal testosterone is one of the newest forms of TRT. This type of testosterone replacement is administered via a small, convex, tablet-like system that adheres to gum tissue in the mouth (above the incisors), where testosterone is hydrated by the buccal mucosa and slowly absorbed. Applied twice daily, each buccal tablet contains 30 mg testosterone. Peak absorption levels are reached within 30 minutes of application; steady state is achieved within 24 hours dropping below normal 2 to 4 hours after the tablet is removed. Comparable to other transdermal delivery systems, buccal administration maintains testosterone at levels within the same physiologic range as testosterone patches and gels. Similar to transdermals and injectable solutions, buccal testosterone avoids the first-pass effect of hepatic metabolism, as it is transported from the buccal venous system directly into the superior vena cava – the large vein which returns blood to the heart from the head, neck and both upper limbs. Associated adverse effects range from mild to moderate including: the possible inadvertent swallowing of the tablet which results in decreased testosterone blood level; possible transfer of salivary testosterone to the partners; bitter taste; sensitivity and tenderness near the application site; and irritation of the gum or mouth.

Testosterone Replacement Therapy

Due to the lack of large-scale, long-term studies assessing the benefits and risks of testosterone replacement therapy in men, controversy remains regarding testosterone supplementation. Numerous studies and self reports indicate that TRT may produce a wide range of benefits, which include marked improvement in quality of life, muscle mass, libido and sexual function, mood and cognitive capabilities, body composition, bone density, increased red blood cell count (erythropoiesis), etc. However, the most controversial area is the issue of risk, especially regarding exogenous testosterone’s potential for stimulating prostate. There is little hard and fast evidence to support this particular risk; in fact, there is abundant evidence to support it begin false, but the question still exists and is readily raised by adversaries of hormone therapy. Other possible risks include worsening symptoms of liver toxicity, benign prostatic hypertrophy, excessive erythrocytosis, hyperviscosity, and worsening untreated sleep apnea. Despite this controversy, testosterone supplementation in the United States has increased significantly over the past several years and continues to flourish without any signs of slowing.

To determine if TRT may be the appropriate course of action, one should make a doctor’s appointment to have testosterone levels tested. It should be noted that ranges vary by laboratory, and may be further confounded based on the computational formulas used for measuring values. However, most present day tests are highly accurate, and a physician will review the results with the patient to aid in understanding, and to help with the interpretation of individual profiles. A good physician should also discuss the potential benefits and the risks of TRT. Once a determination for therapy is made, the doctor will outline many of the available options (most of which are listed above) in greater detail, and help to select a sound testosterone preparation based on diagnostic need and patient preferences and lifestyle.

REFERENCE LIST

• Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerg Drugs. 2006;11( 4):685-707.
• American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8(6):440-456. www.aace.com/pub/pdf/guidelines/hypogonadism.pdf.
• Schubert M, Minnemann T, Hübler D, et al. Intramuscular testosterone undecanoate: Pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab. 2004;89(11):5429-5434.
• Harle L, Basaria S, Dobs AS. Nebido: A long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opin Pharmacother. 2005;6(10):1751-1759.
• Mackey MA, Conway AJ, Handelsman DJ. Tolerability of intramuscular injections of testosterone ester in oil vehicle. Hum Reprod. 1995;10(4):862-865.
• Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol. 2000;161(1-2):73-88.
• Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999;84(10):3469-3478.
• Wang C, Berman N, Longstreth JA, et al. Pharmacokinetics of transdermal testosterone gel in hypogonadal men: Application of gel at one site versus four sites: A General Clinical Research Center study. J Clin Endocrinol Metab. 2000;85(3):964-969.
• Darby E, Anawalt BD. Male hypogonadism : An update on diagnosis and treatment. Treat Endocrinol. 2005;4(5):293-309.
• Androgel [package insert]. www.androgel.com/prescribing_info.html.
• Ross RJ, Jabbar A, Jones TH, et al. Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men. Eur J Endocrinol. 2004;150(1):57-63.
• Dobs AS, Matsumoto AM, Wang C, Kipnes MS. Short-term pharmacokinetic comparison of a novel testosterone buccal system and a testosterone gel in testosterone deficient men. Curr Med Res Opin. 2004;20( 5):729-738.
• Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab. 1992;74(3):623-628.
• Tenover JL. The androgen-deficient aging male: Current treatment options. Rev Urol. 2003;5(suppl 1):S22-S28.
• Basaria S, Dobs AS. New modalities of transdermal testosterone replacement. Treat Endocrinol. 2003;2(1):1-9. Androderm [package insert]. Corona, CA: Watson Pharma, Inc.; 2005.
• http://pi.watsonpharm.com/data_stream.asp?product_group=1200&p=pi&language=E.