Testosterone replacement therapy (TRT) is a regimen of physician prescribed testosterones used to treat hypogonadic (low testosterone) symptoms. Testosterone is the primary male sex hormone (androgen), which is also naturally produced in smaller amounts within the female body. Largely produced by and regulated through a joint effort of the glands and organs which make up the Hypothalamic-Pituitary-Testicular-Axis (HPTA), testosterone is the hormone responsible for the normal growth and development of male sex organs, and plays an integral role in: libido; mood; energy level; bone density; cognitive functions like memory and concentration; and secondary sex characteristics such as voice change, bodily hair growth, muscle mass, and fat distribution.1
TRT uses testosterone to support deficient endogenous testosterone levels by either elevating the total hormone levels back into the normal range, or by raising these levels high enough within the normal range to reverse negative hypogonadic symptoms.23 It should be noted that as with all medication use, there are both risks and benefits to TRT.45
Andropause is the popular term for the condition associated with the physical, emotional, psychological and behavioral changes men experience as they age, but it goes by several aliases including late onset hypogonadism, male climacteric andropause, low testosterone, andropause syndrome, and androgen decline in the aging male (ADAM).6 Often considered the male version of menopause, and in some respects that's accurate, andropause is somewhat different.7 More specifically, both conditions represent age-related primary hormone declines, which if untreated can result in a variety of adverse symptoms. Although traditionally attributed to the aging process, many of the negative effects men start experiencing as they get older are caused by a significant decline in testosterone (the primary male hormone) production, resulting in diminished hormonal levels. Hypogonadic, or andropausal, men will frequently notice a gradual loss of energy, decrease in muscle mass, diminished mental focus and memory, increased body fat, reduced stamina, and a noticeable reduction in libido and sexual functioning.8
Of course testosterone is present in both males and females; however, males produce approximately ten times more testosterone than their estrogen-based female counterparts. Testosterone is the male body’s primary natural hormone, and is integral to male development from birth onward with responsibilities which include:9 determining gender, moderating pubertal changes; maintaining male potency (libido & sexual functioning) and; the partitioning of bodily muscle and fat distribution. It is also foundational to a male's sense of well-being, and figures prominently in physiological, biological, and sexual health, while influencing sperm production, stress coping capacity, mental acuity (clarity, memory & recall, concentration & focus), bone density, red blood cell production, and immune system support. So it's easy to see why so many elements of health begin to breakdown as andropause progresses.
The primary difference between menopause and andropause is that of speed. Whereas menopause is a rather sudden, succinct, and more defined change andropause isn't. Its onset, and declining testosterone production, begins around age 30 and progresses (at a rate of approximately one percent per year).10 Researchers estimate the incidences of andropause in our society as follows: ages 40 to 49 at least 2% to 5% of men could be clinically diagnosed with the condition; ages 50 to 59 anywhere from 6% to 30%; ages 60 to 69 between 20% and 45%; ages 70 to 79 from 34% to 70% and; 80 plus at nearly 91%.11 Virtually all men will experience andropause, but not all men will experience hypogonadic symptoms severely enough to seek medical help.10 According to the U.S. Census Bureau, approximately 15 million men have low testosterone levels, of which only 5-10% of these men will seek treatment,11 largely because many don’t realize this condition is correctable.10
Symptoms of Andropause
- Low hemoglobin and possibly mild anemia
- Loss of bone density which increases the risk of osteoporosis, fractures, and breaks
- Declining strength, and reduced lean body mass
- Increased body fat (visceral, adipose, and subcutaneous)
- Lower energy levels, and reduced interest in usual activities
- Atypical cholesterol and lipid values
- Loss of hair thickness and/or amount
- IMS (Irritable Male Syndrome) - mood swings, irritability, depression, anger, and fatigue
- Loss of sexual desire (libido) and/or various forms of erectile dysfunction (ED)
Although the above symptoms are most commonly attributed to andropause, this condition is also driven by your level of stress, quality of nutrition, amount of exercise and the environmental toxins you are exposed to on a daily basis.24 Some of these symptoms can even be caused by other diseases and conditions such as diabetes, thyroid problems, medication side effects, depression, and excessive alcohol use.25 Testing is important to properly diagnose low testosterone levels.
Testing For Andropause
Actually, routine physicals should expose this condition, but when advanced age is present in conjunction with complaints of traditional andropause related symptoms, physicians will typically employ a simple blood test to measure testosterone levels,26 along with the levels of both 'bound' (that which is attached to Sex Hormone Binding Globulin - SHBG), and 'free' (unbound) testosterone.27 Deficiency is usually diagnosed when testing returns a total serum level near or below the established lower limit, which is generally 350 nanograms per deciliter (ng/dl). The blood test should be administered in the morning, prior to daily stressors which can influence testosterone production such as work, exercise, medication, etc. Other measured hormone levels which usually accompany the testosterone measurement include DHEA, FSH, LH, and Estradiol. All blood testing should be conducted from 8:00-9:00 AM, when blood serum concentrations are at their peak.28
The Clinical Rational For Testosterone Replacement Therapy
Testosterone replacement should in theory approximate the natural (endogenous) production of the hormone. The average male produces 4-7 mg of testosterone per day in a circadian pattern, with maximal plasma levels attained in early morning and minimal levels in the evening.29 Ideal testosterone replacement therapy produces and maintains physiologic serum concentrations, without significant side effects or safety concerns.30 There are different variations (preparations, esters, blends, etc.) of synthetic testosterone each with its own unique properties, and respective methods of action.31323334 Here at Empower Pharmacy the most commonly requested testosterone preparations are injectable and transdermal forms.
Intramuscular Injection (IM) testosterone preparations are shot directly into the muscle, and then absorbed into the bloodstream via the capillaries. This is an extremely popular preparation due to its highly accurate dosing, varying time release qualities, and insignificant hepatotoxicity levels.
Testosterone (Enanthate, Cypionate, and Propionate) is approved by the U.S. Federal Drug Administration (FDA) to treat hypogonadism.
- Improves mood, memory, energy, libido, and erectile function; increases muscle mass, strength, and bone density; and reduces subcutaneous, visceral, and adipose fat.835363738394041
- Possible side effects: abnormal liver function test; acne; gynecomastia; halitosis; vivid dreaming, increased appetite; night sweats
Transdermal (Topical) testosterone preparations can be made in cream or gel preparations and are rubbed into the skin and absorbed through it. Transdermals can be provided in different strengths ranging from 10 mg to 200 mg per milliliter. For optimal benefit, twice daily doses are recommended once upon waking, and again later in the day at consistent times.
- Testosterone creams/gels are approved by the FDA to treat hypogonadism.
- Improves...same as IM
- Possible side effects: same as IM
Monitoring Patients on Testosterone Replacement
Patients on testosterone replacement therapy should be monitored to ensure that testosterone levels are within normal ranges.10 The prescribing physician should continually evaluate changes in hypogonadic symptoms, and address treatment side effects. Serum testosterone levels should be checked 5 to 7 hours after application of transdermal delivery systems, when concentrations are highest.10
Men forty and older should have a PSA test prior to therapy, and it should be repeated in 3-6 months, and then checked annually.26 A confirmed increase in PSA >2 ng/mL, or a total PSA >4.0 ng/mL requires urologic evaluation.26 The hematocrit level should also be checked at baseline, at 3-6 months, and then annually. A hematocrit >55% warrants evaluation for hypoxia and sleep apnea, and/or a reduction in the testosterone therapy dosage.26 Hypogonadal men with osteopenia should be having bone mineral density of the lumbar spine and/or the femoral necks tested after one year.
Causes of Low Testosterone
Testosterone deficiency occurs when there is problem with the HPTA, resulting in a condition known as hypogonadism, and is typically due to any of three basic hypogonadic conditions: 1) primary hypogonadism - originates from a problem within the testicles; 2) secondary hypogonadism - originates from a problem within the hypothalamus or the pituitary gland; and 3) idiopathic, or unknown causes. More specifically, these three forms are often caused by:42 TRT, Klinefelter syndrome, undescended testicles, hemochromatosis, testicular trauma, cancer treatment, mumps orchitis, Kallmann syndrome, pituitary disorders, inflammatory disease, HIV/AIDS, some medications, obesity, andropause, cardiovascular problems, chronic illness, alcoholism, cirrhosis, chronic stress, diabetes.
Symptoms Of Hypogonadism
There are a several symptoms associated with low testosterone levels. Such symptoms vary greatly from mild inconveniences like oily skin, to severe disabilities like impotence. Hypogonadic symptoms are often related and can be largely categorized.
Mood & Irritable Male Syndrome - Gradual decline in testosterone levels (andropause) is believed to contribute to the rising rate of depression in older men.12 Irritable male syndrome (IMS) is a condition often characterized by its associated biochemical changes, hormonal fluctuations, stress, and loss of male identity.13 Irritable Male Syndrome includes increased frequency of anxiety, depression, anger, confusion, diminished relationship and sexual life, and a less satisfying overall quality of life.141516
Sexual Dysfunction - There is a direct correlation between declining testosterone levels and reduced sexual function, i.e., diminished: libido; impotence; inability to sustain erection; low semen volume; etc. 4344
Physical Appearance - Two of the primary measures/symptoms physicians use to aid in their physical diagnosis of low testosterone are the recent significant decrease in muscle mass and inversely increased body fat. Physical health measures include body fat percentage, body mass index (BMI), waist-to-height ratio (WHtR), the basal metabolic rate (BMR), surface area, Willoughby athlete weight calculation, etc.4546171819
General Health - Low serum testosterone has been correlated with a variety of overall health, or quality of life diminishing symptoms such as decreased or reduced: cognitive functions like concentration and focus, memory and recall (brain fog); sexual performance; insulin resistance; muscle mass; sleep quality; bone density; stamina; bodily hair; etc.20212223
Diagnosis of Testosterone Deficiency
This condition is diagnosed in a multi-step process, and can be experienced by both genders but is often considered a male condition. The typical sequence of low testosterone diagnosis is self-reporting, standardized questionnaire, analysis of historical information (personal, sexual, and family), physical exam, and blood test.47
The self-report reflects the current status of sexual function and secondary sexual characteristics, such as beard growth, muscular strength, and energy level.48 Hypogonadal men have statistically significant lower:49 incidences of nocturnal erections; degrees of penile rigidity during erection; and frequencies of sexual thoughts, feelings of desire, and sexual fantasies. Furthermore, alterations in body composition such as increased body fat percentage (adipose, visceral, subcutaneous), and reduced muscle mass are frequently reported by hypogonadal men.50
The Androgen Deficiency in Aging Men (ADAM) and the Aging Males' Symptoms scale (AMS) quickly assess patient mood, energy, quality of life (work and play), sleep, and sexuality. These tests are usually administered while the physician is compiling an index of symptoms - pertinent sexual, personal, and family medical information all of which aids the physician in the identification of possible genetic traits and tendencies.515253
Examples of historical profile data include disclosure of50:
- Sexual History - birth genital abnormalities; delayed puberty; nocturnal emissions; sexual activity; erection rigidity; sexual though frequency; diminishing body hair; changes in muscular size, strength, and ability to gain muscle; changes in energy levels
- Personal History - allergic reactions; blood type; past and present major and chronic illnesses; current medications and supplements; surgeries; immunization dates; doctors' names; past positive test results; lifestyle habits (alcohol drinking, smoking, binge eating, etc.); social relationship problems; major life changes
- Family History - cancer; kidney disease; alcoholism; mental illness; diabetes; blood diseases; and other conditions
Proper labs should be drawn to determine a diagnosis, and low testosterone levels are measured via blood test. Although testosterone blood tests vary (especially older ones), a good test uses two samples to measure total testosterone level, and to directly measure or calculate the amount of 'bound' (inactive) testosterone and 'free' (available for function) testosterone within the bloodstream.50 Sex hormone-binding globulin (SHBG) is a liver synthesized glycoprotein that binds with and disables circulating both androgens and estrogens, and is also used in the calculation of testosterone levels.50 Other measured hormone levels typically include DHEA, FSH, LH, and Estradiol.50 All blood testing should be conducted in the morning from 8:00-9:00 AM when blood serum concentrations are at their peak.
The Clinical Rationale For TRT
Testosterone replacement should approximate the natural, endogenous production of the hormone.50 The average male produces 4-7 mg of testosterone per day54 in a circadian, diurnal pattern,5556 with maximal plasma levels attained in early morning and minimal levels in the evening. Ideal testosterone replacement therapy produces and maintains physiologic serum concentrations, without significant side effects or safety concerns. There are different variations (preparations, esters, blends, etc.) of synthetic testosterone each with its own unique properties, and respective methods of action.
Types of Testosterone Replacement Therapy
Ideal testosterone replacement therapy produces and maintains physiologic serum concentrations of the hormone and its active metabolites without significant side effects or safety concerns.57
Oral agents may cause elevations in liver function tests and abnormalities at liver scan and biopsy. Unmodified testosterone is rapidly absorbed by the liver, making satisfactory serum concentrations difficult to achieve. Modified 17-alpha alkyltestosterones, such as methyltestosterone or fluoxymesterone, also require relatively large doses that must be taken several times a day. Due to it's potential for hepatotoxicity, these formulations are not recommended for clinical use.
Intramuscular Injections (IM)
Testosterone preparations are shot directly into the muscle, and then absorbed into the bloodstream via the capillaries. This is an extremely popular preparation due to its highly accurate dosing, varying time release qualities, and insignificant hepatotoxicity levels. Testosterone Cypionate and Testosterone Enanthate are frequently used parenteral preparations that provide a safe means of extended release hormone replacement in hypogonadal men. The kinetics of testosterone enanthate and cypionate are identical. In men 20-50 years of age, an intramuscular injection of 200 to 300 mg testosterone enanthate is generally sufficient to produce serum testosterone levels that are supranormal initially and fall into the normal ranges over the next 14 days. Fluctuations in testosterone levels may yield variations in libido, sexual function, energy, and mood. Some patients may be inconvenienced by the need for frequent testosterone injections. Increasing the dose to 300 to 400 mg may allow for maintenance of eugonadal levels of serum testosterone for up to three weeks, but higher doses will not lengthen the eugonadal period.
Testosterone is approved by the U.S. Federal Drug Administration (FDA) to treat hypogonadism associated with conditions including the failure of the testicles to produce testosterone because of reasons such as genetic problems or chemotherapy. Other examples include problems with brain structures, called the hypothalamus and pituitary, that control the production of testosterone by the testicles.5835363738394041
Testosterone preparations can be made in cream or gel forms and are rubbed into the skin, then absorbed through it.59 Transdermals can be provided in different strengths ranging from 10 mg to 200 mg per milliliter.6059
Monitoring Patients On Testosterone Replacement
Patients on testosterone replacement therapy should be monitored to ensure that testosterone levels are within normal ranges. The prescribing physician should continually evaluate changes in hypogonadic symptoms, and address treatment side effects. Serum testosterone levels should be checked 5 to 7 hours after the application of transdermal delivery systems, when concentrations are highest.61
It is recommended that men forty and older have a Prostate Specific Antigen (PSA) test prior to therapy.61 The PSA test can be repeated in 3-6 months, and then checked annually. A confirmed increase in PSA >2 ng/mL, or a total PSA >4.0 ng/mL requires urologic evaluation.61 The hematocrit level can also be checked at baseline, at 3-6 months, and then annually. A hematocrit >55% may warrant evaluation for hypoxia and sleep apnea, and/or a reduction in the testosterone therapy dosage.61 Hypogonadal men with osteopenia may consider having bone mineral density of the lumbar spine and/or the femoral necks tested after one year.62
Contraindications To TRT
TRT is traditionally contraindicated in men with prostate and bladder conditions which include but may not be limited to: Benign Prostatic Hypertrophy (BPH); cancer or carcinoma of the breast or prostate; and lipid abnormalities. However, the effects of TRT on prostate size and PSA levels in some studies of hypogonadal men were found to be comparable to those in normal men, and PSA levels were within the normal range.63
Note: Patients using testosterone should seek medical attention immediately if symptoms of a heart attack or stroke are present, such as: chest pain, shortness of breath or trouble breathing, weakness in one part or one side of the body, slurred speech.
Abuse of testosterone, usually at doses higher than those typically prescribed and usually in conjunction with other AAS, is associated with serious safety risks affecting the heart, brain, liver, mental health, and endocrine system. Reported serious adverse outcomes include heart attack, heart failure, stroke, depression, hostility, aggression, liver toxicity, and male infertility. Individuals abusing high doses of testosterone have also reported withdrawal symptoms, such as depression, fatigue, irritability, loss of appetite, decreased libido, and insomnia.
- 1. Mehta PH, Josephs RA. (in press). Testosterone. In R. Baumeister & K. D. Vohs (Eds.), Encyclopedia of Social Pschology
- 2. Am J Med. 2001 May;110(7):563-72. Effects of testosterone replacement in hypogonadal men. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL.
- 3. Am J Med. 2001 May;110(7):563-72. Hypogonadism and androgen replacement therapy in elderly men. Basaria S, Dobs AS.
- 4. Ther Clin Risk Manag. 2009 Jun;5(3):427-48. The benefits and risks of testosterone replacement therapy: a review. Bassil N, Alkaade S, Morley JE.
- 5. Drugs Aging. 1999 Aug;15(2):131-42. Risks versus benefits of testosterone therapy in elderly men. Basaria S, Dobs AS.
- 6. Am J Mens Health. 2013 Nov; (6):516-22. Prevalence of andropausal symptoms among Kuwaiti males. Maha AS.
- 7. Rieder A, Kunze M. "Menopause and Andropause-The Socio-Medical Viewpoint". Monopause/Andropause: hormone replacement therapy through the ages - New cognition and therapy concepts: 15-19.
- 8. Aging Male. 2012 Mar;15(1):14-21. The effect of testosterone supplementation on depression symptoms in hypogonadal men from the Testim Registry in the US (TRiUS). Khera M, Bhattacharya RK, Blick G, Kushner H, Nguyen D, Miner MM.
- 9. Sisk C, Lonestein J, Gore A. "Critical Periods During Development: Hormonal Influences on Neurobehavioral Transitions Across the Life Span." Neuroscience in the21st Century. 2013, pp 1715-1752.
- 10. Mulligan T. Andropause: Pathophysiology, Prblems, and Practice Guidelines. Virginia Geriatrics.
- 11. Rieder A, Kunze M. "Menopause and Andropause-The Socio-Medical Viewpoint". Monopause/Andropause: hormone replacement therapy through the ages - New cognition and therapy concepts: 15-19.
- 12. Am J Psychiatry. 1998 Oct;155(10):1310-8. Age-associated testosterone decline in men: clinical issues for psychiatry. Sternbach H.
- 13. Reprod Fertil Dev. 2001;13(7-8):567-76. The irritable male syndrome. Lincoln, GA
- 14. Arch Esp Urol. 2013 Sep;66(7):729-736. Patients with testosterone deficit syndrome and depression. Khera M.
- 15. Endocr J. 2012 Dec 28;59(12):1099-105. Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, Uzun O, Bolu E, Saglam K.
- 16. J Clin Endocrinol Metab. 2000 Jan;85(1):60-5. Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. Grinspoon S, Corcoran C, Stanley T, Baaj A, Basgoz N, Klibanski A.
- 17. Int J Obes Relat Metab Disord. 2003 May; 27(5): 610-6 A biometric study of basal metabolism in man. Harris J, Benedict F.
- 18. World J Mens Health. 2013 Aug;31(2):126-135. The Relationship between Testosterone Deficiency and Men's Health. Tsujimura A.
- 19. Eur J Endocrinol. 2013 May 2;168(6):829-43. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Corona G, Rastrelli G, Monami M, Saad F, Luconi M, Lucchese M, Facchiano E, Sforza A, Forti G, Mannucci E, Maggi M.
- 20. J Sex Marital Ther. 2011;37(4):243-54. Androgen replacement therapy improves psychological distress and health-related quality of life in late onset hypogonadism patients in Chinese population. Zhang XW, Liu ZH, Hu XW, Yuan YQ, Bai WJ, Wang XF, Shen H, Zhao YP.
- 21. Chin Med J (Engl). 2012 Nov;125(21):3806-10. Short term testosterone replacement therapy improves libido and body composition. Andrade ES Jr, Clapauch R, Buksman S.
- 22. Arq Bras Endocrinol Metabol. 2009 Nov;53(8):996-1004. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Kapoor D, Goodwin E, Channer KS, Jones TH.
- 23. Eur J Endocrinol. 2006 Jun;154(6):899-906. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR.
- 24. Bansal VP. "Andropause". Journal of Universal College of Medical Sciences. 2013;1(2):54-68.
- 25. Bansal VP. "Andropause". Journal of Universal College of Medical Sciences. 2013;1(2):54-68.
- 26. Casulari L, Motta L. "Diagnostic of Andropause: a problem not yet Solved". Arq Bras Endocrinol Metab. 2008;52(9):1401-2.
- 27. Asian J Androl. 2013 Dec 19. Late-onset hypogonadism: Current concepts and controversies of pathogenesis, diagnosis and treatment. Huhtaniemi I.
- 28. Mulligan T. Andropause: Pathophysiology, Prblems, and Practice Guidelines. Virginia Geriatrics.
- 29. Hayes L et al. "Diurnal Variation of Cortisol, Testosterone, and Their Ratio in Apparently healthy Males". Sport Spa;9(1):5-13.
- 30. Winters S. "Current Status of Testosterone REplacementTherapy in Men". Archives of Family Medicine. Jun 1999;8:257-63.
- 31. https://empowerpharmacy.com/drugs/testosterone-cream.html
- 32. https://empowerpharmacy.com/drugs/testosterone-cypionate-injection.html
- 33. https://empowerpharmacy.com/drugs/testosterone-enanthate-injection.html
- 34. https://empowerpharmacy.com/drugs/testosterone-propionate-injection.html
- 35. J Affect Disord. 1998 Mar;48(2-3):157-61. Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. Seidman SN, Rabkin JG.
- 36. J Sex Med. 2009 Jul;6(7):2049-57. Hypogonadism, decreased sexual desire, and long-term depression in middle-aged men. Hintikka J, Niskanen L, Koivumaa-Honkanen H, Tolmunen T, Honkalampi K, Lehto SM, Viinamäki H.
- 37. J Clin Endocrinol Metab. 2000 Aug;85(8):2839-53. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N.
- 38. J Clin Endocrinol Metab. 2000 Aug;85(8):2670-7. The sexual effects of testosterone replacement in depressed men: randomized, placebo-controlled clinical trial. Seidman SN, Roose SP.
- 39. J Sex Marital Ther. 2006 May-Jun;32(3):267-73. Improved sexual function with testosterone replacement therapy in hypogonadal men: real-world data from the Testim Registry in the United States (TRiUS). Khera M, Bhattacharya RK, Blick G, Kushner H, Nguyen D, Miner MM.
- 40. J Sex Med. 2011 Nov;8(11):3204-13. The effects of treating male hypogonadism on couples' sexual desire and function. Conaglen JV, Conaglen HM.
- 41. J Sex Med. 2009 Feb;6(2):456-63. Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. Amiaz R, Pope HG Jr, Mahne T, Kelly JF, Brennan BP, Kanayama G, Weiser M, Hudson JI, Seidman SN.
- 42. The Mayo Clinic Mayo Foundation for Medical Education and Research Male hypogonadism http://www.mayoclinic.com/health/male-hypogonadism/DS00300/DSECTION=causes
- 43. Rev Urol. 2000 Spring; 2(2): 122–128. Relationship Between Testosterone and Erectile Dysfunction. Rajfer, Jacob.
- 44. Endocrine Society. 2013 July; Online. Male Sexual Function and Its Disorders: Physiology, Pathophysiology, Clinical Investigation, and Treatment. Kandeel F, Koussa V, Swerdloff R.
- 45. The Journal of North American Menopause. 2003 Sep-Oct;10(5):390-8. Definition, categories, and computation of the body mass index (BMI) National Heart, Lung, and Blood Institute (NIH). U.S. Department of Health and Human Services
- 46. Am J Clin Nutr. 2002 Oct;76(4):743-9. Waist circumference and obesity-associated risk factors among whites in the third National Health and Nutrition Examination Survey: clinical action thresholds. Zhu S, Wang Z, Heshka S, Heo M, Faith MS, Heymsfield SB.
- 47. Bassil N, et al. "The benefits and risks of testosterone replacement therapy: a review". Therapeutics and Clinical Risk Management. 2009;5:427-48.
- 48. Health Technology Assessment Program. Testosterone Testing: Final Evidence Report. 6 Feb 2015.
- 49. AACE Hypogonadism Task Force. "American Association of Clinical Endocrinologists: Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male patients-2002 Update". Endocrine Practice.Nov 2006;8(6):439-456.
- 50. Bassil N, et al. "The benefits and risks of testosterone replacement therapy: a review". Therapeutics and Clinical Risk Management. 2009;5:427-48.
- 51. Int J Impot Res. 2010 January; 22(1): 20–24. The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism O Mohamed, R E Freundlich, H K Dakik, E D Grober, B Najari, L I Lipshultz, M Khera.
- 52. Eur Urol. 2004;46:80–87. The Aging Males' Symptoms scale (AMS) as outcome measure for treatment of androgen deficiency. Moore C, Huebler D, Zimmermann T, Heinemann LA, Saad F, Thai DM.
- 53. Rev Urol. 2003;5 Suppl 1:S11–S15. Development of an index to evaluate symptoms in men with androgen deficiency. O'Leary, MP.
- 54. "Frequently Asked Qeustions about Andropause (Male menopause) and Testosterone Replacement Therapy." Apothecary Options. Web.
- 55. Hayes et al. "Diurnal Variation of Cortisol, Testosterone, and their Ratio in Apparently healthy males". Sports Spa. 9(1):5-13.
- 56. Gettler L et al. "Salivary Estradiol and Testosterone in Filipino Men: Diurnal Patterns and Relationships with Adiposity". American Journal of Human Biology. 2014;26:376-383.
- 57. Am J Med. 2001 May;110(7):563-72. Effects of testosterone replacement in hypogonadal men. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL.
- 58. Aging Male. 2012 Mar;15(1):14-21. The effect of testosterone supplementation on depression symptoms in hypogonadal men from the Testim Registry in the US (TRiUS). Khera M, Bhattacharya RK, Blick G, Kushner H, Nguyen D, Miner MM.
- 59. "Draft Guidance on Testosterone". Food and Drug Administration. Apr 2013; Revised Nov 2013.
- 60. J Clin Endocrinol Metab. 2000 Aug;85(8):2839-53. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N.
- 61. Want C, et al. Transdermal Testosterone Gel Improves Sexual Function, Mood, Muscle Strength, and Body Composition Parameters in Hypogonadal Men". Journal of Clinical Endocrinology & Metabolism. 2000;85(8):2839-2853.
- 62. Eckhard L et al. "Effects of testosterone rplacement therapy on cortico and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men". Europena Journal of Endocrinology. 1998;138:51-58.
- 63. Clin Endocrinol (Oxf). 1994 Mar;40(3):341-9. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Behre HM, Bohmeyer J, Nieschlag E.