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Testosterone, or T, is the primary circulating sex hormone in males and is critical to the development and maturation of reproductive tissues as well as other secondary male characteristics such as muscle growth and bone density. Synthesized in the gonads of both males (testis) and females (ovaries), testosterone chordates bound to sex hormone binding globulin ("SHBG", ~60%), loosely bound to albumin, a protein in the blood that binds to testosterone (~40%), or as a free molecule (~1%). Once circulating, testosterone enters cells directly and activates a network of proteins that ultimately result in metabolic conversions, which in turn produce observable effects. The concentration of circulating testosterone can vary drastically over time or between individuals and can be dependent on genetic factors, other medical conditions, lifestyle behaviors, and/or concurrent medication administration. Although large variability exists, the effects of testosterone are also determined by a number of factors including the amount of steroid penetration, sensitivity of enzymes and cellular proteins to the hormone, and the action of genomic receptors at the cellular level. As a result, assessing clinically low, or potentially high, levels of naturally occurring testosterone often requires a number of quantitative tests in conjunction with clinical evaluations.
Low serum testosterone causes significant clinical impact and can result in erectile dysfunction, low libido, decreased muscle mass and strength, increased body fat, decreased bone density, decreased vitality and depressed mood. Furthermore, low serum testosterone concentrations have been found to be an independent predictor of a number of cardiovascular risk factors including obesity, abnormal lipid levels, hypertension, type 2 diabetes, and systemic inflammation. Well-designed, prospective clinical trials have determined that low testosterone levels are also independently associated with mortality risk.
Hypogonadism typically refers to a permanent deficiency of sex hormones rather than a temporary deficiency that may be related to acute/chronic illnesses or other medical, personal, or environmental factors. Primary hypogonadism describes disease states that intrinsically affect the gonads. Examples of these include the genetic disorders, Turner syndrome and Kleinfelter syndrome. Secondary hypogonadism refers to disease states that affect gonadal-related structures such as the hypothalamus and pituitary gland that directly impact the development of gonads and as such the release of testosterone and other sexual hormones. Kallmann syndrome, in which patients fail to undergo all of the changes associated with puberty, is a type of secondary hypogonadism. Although a number of inherited diseases are known to affect the gonads either directly or indirectly, it is generally believed that the majority of individuals with hypogonadism develop the condition as a result of age-related declines in testosterone or other acquired conditions.
Prevalence of Hypogonadism and Associated Conditions
Testosterone levels in men decline with age, at a rate of about 1% per year beginning at about 40 years old.3 Epidemiological studies have determined that total testosterone follows an age-related decline with mean serum concentration at the age of 75 years approximately two thirds that at 25 years4. Because naturally occurring testosterone exists at low concentrations, with normal testosterone levels in the range of 300 to 1080 ng/dL automated platform-based assays have been found to lack specificity and are prone to inter-lab variability. The lack of reliable laboratory tests is complicated further by the inter-individual variability seen in an unaffected population. Thus, in order to accurately diagnose hypogonadism in a male, at least two morning serum testosterone levels are performed in conjunction with a clinical assessment of patient symptoms. Patients can only be diagnosed when they present with symptoms that are directly related to low morning serum testosterone level.
According to reports, approximately 74% of chronic opioid users5, 50% of AIDS patients6, 52% of obese men7, 50% of diabetic men7,8 have low testosterone.
Other causes of lowered testosterone levels include: injury, infection, or loss of the testicles; chemotherapy or radiation treatment for cancer; genetic abnormalities such as Klinefelter's Syndrome (extra X chromosome); hemochromatosis (too much iron in the body); dysfunction of the pituitary gland; inflammatory diseases such as sarcoidosis (a condition that causes inflammation of the lungs); chronic illness; chronic kidney failure; liver cirrhosis; stress; and, alcoholism.
3Feldman HA, et al. J. Clin Endocrinol Metab 2002; 87 (2):589-98
4Myers et al. Rev Urol 2003; 5(4) 216-226
5Daniell HW., J Pain. 2002; 3:377-384
6Dobs AS. Baillière’s Clin Endocrinol Metab. 1998; 12:379-390
7Mulligan T, et al. Int J Clin Pract. 2006;60:762-769
8Bodie J, et al. J Urol. 2003;169:2262–2264
9Jackson JA et al., AM. J. Med. Sci. 1992,304 (1) 4-8
Testosterone Replacement Therapy Market
Nearly 500,000 new cases of low testosterone are expected per year in the US as the male population ages.10 Approximately 39% of men over the age of 45 have low testosterone (hypogonadism).11 Based upon this prevalence rate and the U.S. Census Bureau's 2010 estimate that there are 50 million men between 45 and 75 years old, approximately 19 million men in the US may have low testosterone.12 Only 12% of the men with low testosterone receive testosterone replacement therapy according to a study published in Archives of Internal Medicine in 2008. Sales for male testosterone products in the U.S. were $2.0 billion in 201513 and there were approximately 6.2 million prescriptions in 2015.13
Testosterone replacement therapies have been commercially available in the United States for over 70 years and have followed a progression of delivery systems that included subcutaneous, or under-the-skin, intramuscular, transdermal patch, and finally topical gels, which initially surfaced in 2000, and creams. In 2014, a long acting intramuscular injection and an intranasal delivery system for testosterone were approved.
Currently, the U.S. TRT market consists of therapies that exist in four forms:
- intranasal; and
- buccal tablet, which is a tablet shaped patch applied to the upper gums.
Although transdermal patches were previously the most desirable application type, gel-based TRT has gained increasing popularity due to improved skin tolerability. Despite becoming a popular approach to male hypogonadism treatment, topical gels are not without limitations. Topical gels place women and children at risk of testosterone transference (secondary exposure to gels), which has prompted the FDA to add black box warnings relating to testosterone transference in the label of approved topical products. Despite these limitations, gels have continued to demonstrate significant market penetration.
The male testosterone market was $2 billion in 2015 according to IMS Health data. Additionally testosterone replacement prescriptions were approximately 6.2 million in 2015 according to IMS Health data. Injectables are the predominant dosage form in this market in terms of annual prescriptions written although topical gels also have a significant share of total annual prescriptions. The historical growth in the market was driven by increasing recognition by both patients and providers of the prevalence of hypogonadism and its far-reaching medical consequences. Top treatments are marketed by AbbVie, Eli Lilly, and Endo.
10 Journal of Clinical Endocrinology and Metabolism, 2004
11 Mulligan et al. Int J CLin Pract 2006; 60(7) 762-769
12International Journal of Clinical Practice, 2006
13IMS Health Data
1 Bhasin S, Cunningham G, Hayes F, Matsumoto AM, Synder PJ, Swerdloff RS, et. al. J Clin Endorrinol Metab (2010)