What is Testosterone?
In men, testosterone is an androgen that is synthesized and secreted from the Leydig cells while the corpus luteum and adrenal cortex are responsible for synthesis and secretion of testosterone in women. Also, testosterone precursors such as androstenedione and DHEA are weak androgens that can be converted to testosterone peripherally. In addition, testosterone secretion is higher in men than women in almost all stages of life. During the first trimester, the fetal testes start to secrete testosterone and by the beginning of second trimester the fetal testosterone concentration is around 250 ng/dL. However, the level of testosterone declines by end of the second trimester, but again the level goes back up to 250 ng/dL during birth. During puberty around 12 to 17 years old, the concentration of testosterone increases so that by the time of adulthood the level has been reached to 300 ng/dL to 800 ng/dL in men and 30 to 50 ng/dL in women. This high concentration in men is what makes a huge difference between women and men both physiologically and mentally .
*Peter Synder, Androgens and the Male Reproductive Tract
BENEFITS OF TESTOSTERONE REPLACEMENT THERAPY MEDICATIONS
Restoring testosterone level to the normal range can improve mood, energy levels, sexual function, lean body mass and muscle strength, bone mineral density, cognition and some benefits on cardiovascular risk factors. Testosterone replacement therapy medications can be personalized for every patient according to their specific prescription.
Long-term follow-up on patients with hypogonadism treated with testosterone demonstrated a significant higher (p<0.0001) libido self-assessment compared to those that were not treated with testosterone. Furthermore, testosterone supplementation is well known for enhancing body composition, muscle mass, bone density, and erythropoiesis.
More specifically, testosterone replacement therapy has been shown to enhance positive moods, such as feelings of wellness and friendliness, while reducing negative feelings including anger, nervousness, and irritability.
The Metabolism and Effect of Testosterone
Two active forms of testosterone are derived from 5-alpha reductase and aromatase, which will lead to the production of dihydrotestosterone and estradiol, respectively. Increased level of active testosterone in the systemic circulation affects many tissues. For instance, the phallus enlarges in length and width, the prostate start secreting fluid, the scrotum become rugated, the skin becomes coarser, sexual hair grows, muscle mass increases and so many other effects. The serum concentration of testosterone and characteristics of men are maintained during early adulthood and midlife; however, there is a gradual development of male pattern baldness and hear recession at this time of life. As men age, the concentration of testosterone significantly, which leads to decreased energy, libido, muscle mass, and bone mineral density.
*Peter Synder, Androgens and the Male Reproductive Tract
Testosterone deficiency happens as the result of failure of testes to produce and secrete enough testosterone. Hypergonadotropin hypogonadism leads to low level testosterone and elevated level of gonadotropin as the result of primary testicular failure. In the secondary, hypogonadotropin hypogonadism, the level of both gonadotropin and testosterone are low as the result of pituitary gland failure. Men with primary or secondary hypogonadism are candidates for testosterone replacement therapy .
Diagnosis of Testosterone Deficiency
Medical history, Physical exam, and Laboratory Evaluation
The medical history should include questions about developmental abnormalities at birth, the extent of virilization at the time of puberty, and current status of sexual function and secondary sexual characteristics such as bread growth, energy level, and muscular strength. Men with hypogonadism have significant reduction in incidence of nocturnal erections, frequency of sexual thought, degree of penile rigidity, and sexual fantasies. Also, changes in adipose tissue distribution and increase in percent body fat are most commonly seen in these patients as well as reduction in bone mineral density.
The testosterone level is usually measured in the morning and when the concentration of total testosterone is low and/or patient complains of reduced libido, it is a must to measure the prolactin level. In addition, the serum LH level is also measured when the prolactin level is normal in order to differentiate between intrinsic testicular failures from hypothalamic abnormality. So, when the concentration of LH is high, the patient has primary testicular failure, which is a good candidate for testosterone replacement therapy.
* Nazem Bassil, The Benefits and Risks of Testosterone Replacement Therapy’ 2009
Testosterone Replacement Therapy
The average concentration of testosterone in male is around 4-7 mg per day. The goal of testosterone replacement therapy is to approximate the natural, endogenous production of hormone. The rational for using this therapy includes stabilizing bone density, increasing muscle strength and decreasing adipose, enhancing energy and mood, and restoring secondary sexual characteristics, libido and erectile function .
Several types of testosterone replacement therapies are available in the market including tablets, injections, transdermal patches, oral, pellets, and buccal preparations of testosterone .
- Oral agents:
- The oral form of 17-alpha-alkylated androgen should not be used due to liver toxicity and deleterious effects on level of LDL and HDL cholesterol. Due to these side effects these oral preparations roughly constitute third of the testosterone prescriptions filled in the United States 
- Intramuscular injection:
- Testosterone cypionate and enanthate are considered as safe parenteral preparations for hormonal replacement in hypogonadal men. In order to be effective, testosterone is esterified to inhibit its degradation and to be more soluble in oil-based injection vehicles. In men between 20-50 years old, 200-300 mg testosterone enanthate injection is sufficient to produce testosterone level that is supranormal initially and decline to the normal range for the next 14 days. These fluctuations in level of testosterone can lead to variations in libido, sexual function, energy, and mood. However, some patients do not want frequent injection and prefer a higher dose of 300 to 400 mg and less frequent, which will not lengthen the eugonadal period  
- Transdermal system:
- Testosterone transdermal system exists as either scrotal or non-scrotal skin patch, and more recently as gel preparation, which provides continuous delivery of testosterone for 24 hours. Each type has to be applied each day that delivers 5 to 10 mg of testosterone. Scrotal patches produce higher level of serum dihydrotestosteone due to high 5-alpha-reductase enzyme activity of scrotal skin. The advantage of this system is ease of use and maintenance in addition to their efficacy in providing testosterone replacement therapy.
- Sublingual and Buccal
- The sublingual formulation is cyclodextrin-complexed testosterone that is rapidly absorbed into the circulation upon its release from the cyclodextrin shell. It has been suggested that this formulation has a relatively food therapeutic effect.
- Subdermal implants
- This system still offers the longest duration of therapy with prolonged zero-order, steady-state delivery lasting 4 to 7 months. The testosterone is implanted at standard dose of four 200 mg pellets (800 mg) at intervals of 5 to 7 months. However, there is a high risk of infection at the site of implant.
Monitoring Patients on Testosterone Therapy
The physician prescribing testosterone therapy should monitor the patient to make sure the testosterone level is within the normal range. One of the ways of assessment is the evaluation of any changes in the clinical symptoms and signs of testosterone deficiency such as acne and increase in breast size. The circulating testosterone concentration should be checked every three to twelve hours after transdermal application and three to four months prior to the next injection for injectable testosterone. As a result, levels exceeding 500 ng/dL or are less than 200 ng/dL needs dose/frequency adjustment.
The testosterone is primarily metabolized and inactivated by the liver and has an extensive first-pass metabolism. As a result, oral formulation of testosterone is not recommended .
- Elimination half-life
- 5.7 hours for buccal
- 2 to 3 hours for oral
- 70.8 days for subQ implanted pellet
- 49.7 to 58.5 minutes for sublingual
Contraindication to Testosterone Use
One of the main contraindication to using testosterone therapy is in men with carcinoma of the breast or known or suspected carcinoma of the prostate, as it may cause rapid growth of the tumor. Also, testosterone should not be used in men with severe benign prostatic hypertrophy-related bladder obstruction. In addition, testosterone therapy is inappropriate to improve the athletic performance, as it is potentially dangerous. In addition to worsening the symptoms of benign prostatic hypertrophy and increasing the risk for prostate cancer, testosterone therapy may cause liver toxicity and tumor, gynecomastia, infertility, skin diseases, and may worsen sleep apnea and congestive heart failure.
Safety Issues with Testosterone Replacement Therapy
Although testosterone may be used in aging men with hypogonadism, this hormone should not be administered to men with normal testosterone level with intent of reversing aging process. Also, the therapy may be associated with azoospermia, lipid abnormalities, polycythemia, sleep apnea, and prostate changes.
 Snyder, Peter J.. "Androgens and the Male Reproductive Tract." Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Eds. Laurence L. Brunton, et al. New York, NY: McGraw-Hill, , http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=172482470.
 Hellstrom, Wayne JG. "Testosterone replacement therapy." The Scientific World Journal 4 (2004): 142-149.
 Bassil, Nazem, Saad Alkaade, and John E Morley. “The Benefits and Risks of Testosterone Replacement Therapy: A Review.” Therapeutics and Clinical Risk Management 5 (2009): 427–448. Print.
 Testosterone. Micromedex Solution. Truven Health Analytics, Inc. Ann Arbor, MI. Available at: https://www-thomsonhc-com.ezproxy.cnsu.edu. Accessed September 28, 2018.