The connection between the testes and vigor has been known since the first written medical texts. Roman and Greek doctors described the loss of sexual drive, erectile function and physical decline seen in castrated men. Ancient Greek texts prescribed the ingestion of bull testicles to treat loss of energy and to enhance sexual performance.
In the 1800's, physicians described beneficial responses to testicular extracts and even attempted testicular transplants. In 1935 testosterone purification became possible. The physicians who accomplished this feat received the Nobel Prize in 1939. In 1940 and 1944, the first American published reports of testosterone use for the male climacteric were published. The latter article was published in The Journal of the American Medical Association.
Dosing Regimens
Until the 1970's, testosterone was given according to subjective criteria and with generalized dosing regimens. When the ability to measure testosterone levels became reality, data showed that testosterone levels decline with age. Studies found that after age 30, testosterone levels may decline an average of 2% a year.
This decline is a result of several concurrent changes. First is a decline in testosterone production consistent with a decline in Leydig cell numbers in the testes and decreasing activity of the enzymes that produce testosterone. There is also a diminished response to pituitary signals that normally initiate testosterone production and diminished coordination of the release of the pituitary signals that are produced, decreasing any chance for the testes to continue a normal pattern of testosterone secretion.
Finally, sex hormone-binding globulin (SHBG) level increases with age. This protein links irreversible to testosterone, so even though testosterone may be present, it is not "free" or biologically available to do what it needs to do. Increasing SHBG level, therefore, reduces free testosterone to a greater extent than the reduction seen in overall testosterone. Thus, less total testosterone production in conjunction with an increasing binding protein level acts in tandem to synergistically depress free functional testosterone levels. Another cause for premature reduction of testosterone production is the viral illness, Mumps.
Almost every child will experience this illness and will fully recover without problems. In a small proportion of cases the testicles become inflamed in a process called Orchitis. It is believed that either the direct effect of the virus or the prolonged elevated temperature associated with the illness causes damage to the testosterone producing ability of the glands. This leads to a premature shut down in production of testosterone.
How To Tell If Your Mr. T Has Gone South!
Testosterone is an anabolic (or building) hormone. The age-related decline in testosterone levels is associated with the following identifiable signs or symptoms:
- A decline in muscle mass and strength. Loss of muscle volume and tensile strength are hallmarks of aging. Diminishing testosterone levels directly correlate with a decrease in the synthesis rate of muscle proteins, formation of contractile structures and the force generating capabilities of muscle cells. Declines in muscle mass are also correlated with increased risk for falls and fractures.
- Increase in body fat mass, particularly abdominal fat and pectoral fat. Sometimes, Gynecomastia, (enlargement of breast tissue in men) may occur. Decreases in testosterone are also associated with increasing levels of leptin. Leptin is a peptide hormone produced by fat cells and its circulating levels are directly reflective of an individual's fat mass. Adequate testosterone levels and lean mass are inversely correlated with leptin levels.
- Decrease of bone mass. Studies indicate that age and associated declines in testosterone levels correlate with bone loss in men. Declines in Estradiol and testosterone levels are associated with bone loss in women as well, and this phenomenon appears at an earlier age and at a more rapid rate compared to men. Up to 30% of men aged 60 and over may become osteoporotic. One in 6 will fracture a hip at some point in his life. Women are hormonally and statistically more complex than men. Female hormone replacement studies do not separate the effects of estrogens and testosterone, but do show benefits of proper overall hormone replacement programs. An unsupplemented woman will at ages 60 - 80, show a 50% reduction in her original bone mineral density and 1 in 4 will suffer a vertebral or hip fracture.
- Decline in sex drive and frequency of sex thoughts. Interestingly, this decline precedes declines in actual performance.
- Increased frequency of erectile dysfunction in men and diminished sexual response and pleasure in women.
- Decreased sense of overall well being, perception of energy level and vigor. These types of complaints, along with non-specific irritability, are frequently the first symptoms associated with declining testosterone levels, but are the most often overlooked or attributed to stress or "not being as young as you used to be."
- Decline in stamina and exertional performance. A graph of the declines in testosterone and growth hormone levels can be placed over a graph of the percentage of professional athletes still performing at a given age, with essentially identical shapes. Other "performance-minded" individuals, like business executives and people whose careers demand multi-tasking or complex problem solving skills, also frequently note similar functional declines.
- Decline in cognitive skills, concentration and memory. Studies show declining testosterone level is strongly associated with cognitive decline and diminished visual-spatial memory.
- Coronary artery disease and cholesterol derangement. In population studies, low levels of testosterone are associated with increased risk of atherosclerotic cardiac disease. Older men treated with testosterone can show decreases in total cholesterol and LDL (bad cholesterol). Low testosterone levels are also correlated with a greater degree of atherosclerotic obstruction when coronary artery disease is present.
The goal of testosterone replacement therapy is to minimize, prevent or reverse the affects of our age related decline. The beneficial effects of attaining healthy testosterone levels are seen for both men and women and are essentially the inverse of the aforementioned list of problems. Of course, the goals for testosterone level are appropriately lower for women.
Testosterone Therapy
While the clinical indicators of testosterone decline may give a care provider a notion that an individual may be a candidate for testosterone replacement, objective measures must be obtained to properly institute and manage therapy and rule out and address accompanying medical problems.
To adequately measure testosterone levels, both total and free testosterone studies should be evaluated. For males: a level of 260-1,000 ng/dl is given as the normal laboratory range from men aged 20-70. For females, this range is 15-70 ng/dl. Free testosterone levels average approximately 2% of the total, 50-210 pg/mi for men and 1-10 pg/mi for women. Free testosterone is the slightly more valuable of the two, as it reflects the amount of testosterone available to perform useful work at any one moment.
A decline of 70% from more youthful levels may produce many or all of the previously mentioned clinical problems, yet is declared "within normal range". A more accurate approach would be to use the normal range seen from age 30-35 (approximately 700-900 ng/dl for men, and 50-70 ng/dl for women), and try to maintain these levels over time rather than let them continue to decline.
Our (The Millennium Health Group) approach is to arrest falling levels and prevent their decline from the start. Testosterone levels can give us enough clinical information to make a decision as to whether or not replacement or supplementation is indicated, but ideally would take place in the context of other hormonal and laboratory studies as well.
A prostate specific antigen (PSA) measurement must accompany testosterone levels at the time of an initial evaluation. This is in order to screen for any pre-existing prostate disease, to direct any pre-requisite work-up of elevated level that may be associated with prostate disease and to be used as a baseline for future program follow-up.
Other studies, such as thyroid hormones, growth hormone (hGH), lutenizing hormone (LH) dihydroepiandrosterone (DHEA), blood count, lipid profiles and other laboratory and metabolic markers - such as body composition and bone density - all play roles in maximizing a testosterone replacement program.
Optimally, a testosterone delivery method should be clinically effective in correcting the signs and symptoms of testosterone decline and produce predictable and reproducible physiologic levels of testosterone and estradiol. Testosterone can be converted to estradiol by an aromatase enzyme. This is a relevant concern in men because some men seem to have a much more hard-wired connection between testosterone and estradiol, so any intervention that raises testosterone levels may concomitantly raise estradiol levels in an undesired fashion.
With proper follow-up of levels, this is easily identified and avoided. The raising of serum levels of dihydrotestosterone (DHT) does not seem to be clinically important. DHT is the agent associated with male-pattern baldness and prostate disease, and any tissue that picks up testosterone is able to convert it to DHT inside the cell, yielding the benefits of DHT without requiring any certain serum level and avoiding potential side effects.
Testosterone is available directly in oral, injectable, topical and implantable formulations; and may also be supplemented indirectly by the administration of human chorionic gonadotropin, which stimulates testosterone production by the testes. One oral preparation that is useful for helping normalize testosterone levels in women is DHEA. Men do not convert DHEA into meaningful levels of testosterone, but women may.
A frequent first step in improving testosterone levels in women is to optimize DHEA levels and re-check testosterone after 5-7 weeks, then use that value as the definitive criteria for instituting testosterone therapy.
The injected form of testosterone is not associated with the above-mentioned undesirable effects of oral androgen administration and is available in a formulation - Testosterone Enanthate - that allows a relatively long biological effect time and typically requires a dosage interval of only once each week. For males whose testicles are no longer able to produce testosterone in meaningful amounts, this is the replacement therapy of choice.
Testosterone pellets have also been developed that can provide augmented serum testosterone levels for up to six months. However, these pellets require a surgical procedure for implantation and removal, and once they are placed, do not allow a means for tailoring dosage based on an individual's response.
Testosterone formulations are also available for topical placement. These formulations allow testosterone absorption through the skin. This is the therapy of choice for raising testosterone levels in women.
We do not use topical replacement much for men as this method produces excessive levels of DHT. A reductase enzyme converts a lot of topically-delivered testosterone to DHT. This may heighten prostate and hair follicle response to DHT, rather than testosterone. Testosterone patches have also been associated with other minor disadvantages, low obtainable maximum serum testosterone levels, difficulties with the area of skin required to apply creams to achieve therapeutic levels in men and local skin reactions.
Mild to moderate reactions occur in as many as 50% of men using some formulations of the skin patch, which have been shown in studies to produce a 30-50% failure rate in clinical applications.
The very small amounts of testosterone required to raise testosterone levels in women have not been associated with these problems. Patches may seem user-friendly compared to injections, but we have found their use limited.
HCG And LH
An interesting new way of enhancing testosterone has been through the use of human chorionic gonadotropin (hCG). In the testosterone control pathways, the pituitary gland releases a hormone called leutinizing hormone (LH). LH travels to the testicles and stimulates the Leydig cells to synthesize and to secrete testosterone.
LH acts as a "thermostat" for testosterone control. As the testicles produce testosterone, levels in circulation rise. Once these levels reach a certain point, the pituitary will decrease secretion of LH and the signal to the testicles to produce testosterone is diminished. As testosterone production decreases, the pituitary will sense the drop and will resume secretion of LH.
A good analogy would be the thermostat on a furnace with testosterone being the temperature; higher testosterone turns off the thermostat, lower testosterone turns on the thermostat.
We are now able to acquire and administer synthetic LH. HCG binds the same receptors and as the same binding affinity for these receptors that LH does. Administration of HCG, therefore, can mimic the effect of LH and increase an individual's testosterone production without directly administering testosterone in men who still have a functional LH/testosterone control loop.
This way of raising testosterone is the most physiologic and is not associated with testicular atrophy that can occasionally be seen with direct testosterone administration. HCG can be administered daily in small doses via a subcutaneous injection, or given twice weekly via the same route. While direct injection of testosterone has a very high success rate, there is approximately a 10-15% failure rate seen in individuals using HCG.
With normal aging, the testicles will at some point stop responding to the LH signal from the pituitary. This is usually associated with a rise in LH levels. An analogy for this would be to consider LH level a sign of the pituitary's appetite for testosterone. The higher the LH level, the greater the appetite; so with many men, as testosterone secretion declines, the LH level rises in response. In some men, this LH rise does not occur.
If testosterone levels do not rise as we follow a patient's program, we know the "disconnect" between the testicles and the pituitary has occurred and this is an indication that, for that individual, direct testosterone supplementation is the appropriate route monitoring testosterone replacement.
Once any testosterone intervention is imitated, adequate and ongoing follow-up is critical. Starting testosterone therapy is only the first step in a replacement program. Continued monitoring is the hallmark of a truly safe and successful program.
As mentioned previously, or some men, a rise in testosterone produces an exaggerated rise in Estradiol levels, if this occurs, it can blunt or negate the beneficial effects of testosterone and may even produce breast enlargement (Gynecomastia). If Estradiol levels rise too high, it is important to recognize this and adjust testosterone dose or implement therapy to block the conversion of testosterone to excess Estradiol.
It is also important to follow other metabolic markers that may be associated with testosterone therapy. Hemoglobin and Hematocrit may rise with testosterone therapy and must be monitored over time as well. If testosterone levels are kept too high, we may see derangement in cholesterol metabolism and fluid retention, potentially exacerbating high blood pressure or causing edema. Overly elevated testosterone levels may also hasten the onset of prostatic hyperplasia.
Following laboratory markers over time and adjusting therapy appropriately is a prerequisite for an efficacious and safe testosterone replacement program.
Conclusion
Testosterone levels are directly related to a number of age-related changes, notably: muscle strength, cognitive function, body composition and overall self-perception of energy and vigor. Testosterone replacement therapy enhances muscle strength and lean body mass, decreases leptin and may enhance cognitive function, bone mineral density and have positive effects on the cardiovascular system. Testosterone can be easily administered and monitored as part of a complete proactive health program.
Part 2: Testosterone Question and Answer: Coming in our December (next) issue!
Mark Gordon, M.D,. is duel boarded by the American Academy of Family Physicians and the American Board of Anti Aging Medicine. Dr. Gordon is co-heading our Planet Muscle Advisory Board, with Jose Antonio, Ph. D. He is the founding director of the Millennium Health Centers, Inc., a member of the Millennium Health Group in Encino, California. Additional information about Dr. Gordon and his medical practice can be obtained at his website: still.lookingsharp.com
Special Acknowledgement:
Abraham H. Kryger, M.D., DMD. Dr. Kryger is the author of the Testosterone Conspiracy and he also developed TestoCream and EstroCreme.