Testosterone Replacement

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.

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. It should be noted that as with all medication use, there are both risks and benefits to TRT.

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: 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. Irritable male syndrome (IMS) is a condition often characterized by its associated biochemical changes, hormonal fluctuations, stress, and loss of male identity. Irritable Male Syndrome includes increased frequency of anxiety, depression, anger, confusion, diminished relationship and sexual life, and a less satisfying overall quality of life.

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.

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.

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.

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.


The self-report reflects the current status of sexual function and secondary sexual characteristics, such as beard growth, muscular strength, and energy level. Hypogonadal men have statistically significant lower: 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.

Standardized Testing

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.

Historical Profile

Examples of historical profile data include disclosure of:

  • 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

Blood Testing

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. 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. Other measured hormone levels typically include DHEA, FSH, LH, and Estradiol. 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. The average male produces 4-7 mg of testosterone per day in a circadian, diurnal pattern, 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.

Oral Testosterone

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.

Transdermal (Topical)

Testosterone preparations can be made in cream or gel forms and are rubbed into the skin, then absorbed through it. Transdermals can be provided in different strengths ranging from 10 mg to 200 mg per milliliter.

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.

It is recommended that men forty and older have a Prostate Specific Antigen (PSA) test prior to therapy. 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. 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. Hypogonadal men with osteopenia may consider having bone mineral density of the lumbar spine and/or the femoral necks tested after one year.

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.

 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.