Andropause & Testosterone Replacement Therapy

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 that 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.^[2][3] It should be noted that as with all medication use, there are both risks and benefits to TRT.^[4][5]

Andropause

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 that include: determining gender, moderating pubertal changes; maintaining male potency (libido & sexual functioning), and; the partitioning of bodily muscle and fat distribution.^[9] 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, largely because many don’t realize this condition is correctable.^[10][11]

Andropause Symptoms

The symptoms of andropause are the same as those of non-age related testosterone deficiency, a.k.a. low testosterone, and are characterized by:^{[12][13][14][15][16][17][18][19][20][21][22][23]}

• 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, along with the levels of both ‘bound’ (that which is attached to Sex Hormone Binding Globulin – SHBG), and ‘free’ (unbound) testosterone.^[26][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]

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: 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.^[31]

Hypogonadism Symptoms

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.^[14][15][16]

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.^[32][33]

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.^{[17][18][19][34][35]}

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.^{[20][21][22][23]}

Testosterone Deficiency Diagnosis

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.^[36]

Self-Reporting

The self-report reflects the current status of sexual function and secondary sexual characteristics, such as beard growth, muscular strength, and energy level.^[37] 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.^[38] Furthermore, alterations in body composition such as increased body fat percentage (adipose, visceral, subcutaneous), and reduced muscle mass are frequently reported by hypogonadal men.^[39]

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.^[40][41][42]

Historical Profile

Examples of historical profile data include disclosure of:^[39]

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

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.

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.^[39] 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.^[39] Other measured hormone levels typically include DHEA, FSH, LH, and Estradiol.^[39] 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 Testosterone Therapy

Testosterone replacement should approximate the natural, endogenous production of the hormone.^[39] 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.^[43][44][45] 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.^[2]

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

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.^{[46][47][48][49][50][51][52][53]}

Transdermal (Topical)

Testosterone preparations can be made in cream or gel forms and are rubbed into the skin, then absorbed through it.^[54] Transdermals can be provided in different strengths ranging from 10 mg to 200 mg per milliliter.^[49][54]

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.^[55]

It is recommended that men forty and older have a Prostate Specific Antigen (PSA) test prior to therapy.^[55] 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.^[55] 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.^[55]Hypogonadal men with osteopenia may consider having bone mineral density of the lumbar spine and/or the femoral necks tested after one year.^[56]

Contraindications to Testosterone Therapy

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.^[57]​