The beneficial effects of “testosterone” have been suspected for thousands of years. In 2000 bc, the ancient Indian manuscripts described the ingestion of testicular tissue for the treatment of male impotence. The ancient Egyptians also described the medicinal powers of the testis. In 1889, Charles Brown-Sequard injected himself with an extract of crushed canine and guinea pig testes, and reported improvements in his urinary stream, intellect, and erectile function. In 1920, Serge Vornoff completed the first testicular tissue transplant from chimpanzee to human [1]. In 1941, Butenandt and Ruzicka first described the synthesis of testosterone. In the 1940s, the first subdermal testosterone implants were introduced, and 10 years later the first testosterone esters followed. These esters are the basis of the intramuscular injections that we still use today. In the 1970s, testosterone undeconoate (TU; Andriol Testocaps^®, Organon) became available outside the USA. Currently, TU is in Phase III trials in the USA. In 1994, the first transdermal testosterone was introduced as a patch, known as Testoderm (Alza Corporation), and in 2008, the FDA first approved subdermal testosterone implants.

Androgen deficiency is a serious problem in the older male population, thought to affect approximately 1 in 200 men [2]. Mulligan et al. demonstrated that roughly 39% of men over the age of 45 had an androgen deficiency, using a threshold testosterone level <300 ng/dL [3]. However, not all of these men were symptomatic. In fact, Araujo et al. found that the prevalence of symptomatic androgen deficiency was approximately 4% in men under the age of 50 and 8% in men over the age of 50 [4]. The European Male Aging Study noted that only 2% of men between the ages of 40 and 79 had symptomatic androgen deficiency. Thus, clinicians must exercise caution in selecting patients who should receive treatment.

We recognize that beginning at approximately 20–30 years of age, males experience a decline in total testosterone and free testosterone levels of 0.4% and 1.3% per year, respectively [5]. The common symptoms observed with this decline in serum androgens have not been fully defined, as have the symptoms of declining estrogen levels in women. Signs and symptoms of hypogonadism include changes in bone mineral density [6, 7], muscle strength [8, 9], cognition [10], body composition [11], and sexual function [12].

In order to understand how different testosterone therapies function, one must understand the hypothalamic–pituitary–gonadal axis. The production of testosterone is regulated by luteinizing hormone (LH) from the anterior pituitary. In turn, LH secretion is regulated by gonadotropin-releasing hormone (GnRH), which is secreted from the hypothalamus. GnRH is secreted in a pulsatile fashion and is significantly elevated at the time a boy enters puberty. This elevation in GnRH, and subsequent increase in LH, results in a surge in testosterone and the subsequent development of secondary male sexual characteristics and spermatogenesis.

Testosterone is synthesized by the Leydig cells within the testicles. The testes are not able to store testosterone adequately on their own or convert testosterone into its more potent form, dihydrotestosterone (DHT). This is because the testes lack the enzyme, 5-alpha-reductase, which converts testosterone into DHT, its much more potent form. In order to compensate for this, the testes have high levels of androgen binding protein, which is produced by the Sertoli cells and helps to maintain high intratesticular levels of testosterone [13].

Testosterone levels vary on the basis of a diurnal rhythm, with the highest levels of circulating testosterone occurring in the early morning hours. Studies have demonstrated that the diurnal rhythm of total testosterone that is observed in young men is markedly reduced or absent in older, yet otherwise healthy, men suggesting that these altered diurnal patterns may be a consequence of normal aging [14].

Approximately 2% of circulating testosterone within the blood is unbound and freely enters cells to exert a metabolic effect [15, 16]. The amount of bioavailable testosterone is the sum of the free testosterone and the albumin-bound testosterone [15]. The distinction between bioavailable testosterone and total testosterone (bioavailable plus SHBG bound) may be important when levels of testosterone are being measured in the hypogonadal male. SHBG is synthesized in the liver, and its levels can be increased by hyperthyroidism and cirrhosis, and decreased by hypothyroidism, acromegaly, and obesity [15, 16]. SHBG levels also increase as men age, and these increases can lead to variability in testosterone levels and their impact on biological functions [15, 16].

Use of exogenous testosterone should be discouraged in hypogonadal patients who desire to protect their future fertility potential. A more appropriate approach in such patients is to intrinsically increase their endogenous testosterone. There are several ways to accomplish this; however, all of the options, except for HCG injections, are considered off label.

One option is to initiate use of clomid, 50 mg every other day or 25 mg every day for 3–6 months. Clomiphene citrate is a selective estrogen receptor modulator. A trans isomer of clomiphene citrate is currently in clinical trials in the USA for the treatment of secondary male hypogonadism. Because clomiphene citrate is an estrogen receptor blocker and raises serum FSH and LH levels, it is less effective in raising serum testosterone levels when a patient’s LH and FSH levels are already elevated, as in patients with primary testis failure.

Another method of increasing endogenous testosterone is the use of Arimidex (AstraZeneca). Arimidex is an aromatase inhibitor that blocks the conversion of testosterone to estradiol. This action is especially useful in obese patients who tend to have increased amounts of aromatization occurring in their fatty tissues. In adults, there is concern that long-standing suppression of estradiol may increase the risk of osteoporosis and osteopenia, and lead to joint pain. However, this has not been the case in adolescent young men.

BHCG injections are an alternate method, used to increase endogenous serum testosterone levels. HCG is an LH analog that stimulates Leydig cell production of testosterone. Intramuscular injections vary from two to three times per week and from 1,500 to 3,000 units and sometimes higher. While HCG injections may be beneficial in raising serum testosterone levels and preserving fertility, HCG injections can be expensive and are not covered by insurance. The invasive nature of this medication can deter many patients.

The primary goal of TRT is to restore normal physiologic concentrations of testosterone. The choice method for TRT depends on availability, safety, cost, tolerability, efficacy, and patient and physician preference. A summary of the currently available testosterone delivery formulations is listed in Table 10.1.