Testosterone Modulation for Men & Women 

Ancient Greeks described the connection between the testes and male vigor. They noted the finding associated with male castration and were astute enough to postulate on the decline in vigor, seen with the age-related decline in a man’s testosterone level.

Galen described these findings; in that era, he or others actually prescribed consumption of animal testes in an attempt to restore vigor—although there are no double blind placebo control data from the literature of the time.

Historical Perspective

As extracting skills improved, British physicians in the 1800s used many different testicular extracts with reported clinical responses. They even described cadaveric transplants from younger men’s corpses into older men with some success. In 1930’s America, some of these transplants were attempted, using deceased convicts as donors. In 1935, testosterone was purified, yielding a Nobel Prize for the team accomplishing this feat. 

In 1940, JAMA published the first article, describing the clinical utility of using testosterone to treat symptoms of the “male climacteric.” A subsequent article in 1944 showed similar results. 

From then until the 1970s, testosterone was given according to subjective criteria and with generalized dosing regimens. Once testosterone levels could be measured, it became possible to more accurately assess individual levels as an aid to implementing and precisely monitoring therapy. With the ability to measure testosterone came data, showing that testosterone levels decline with age. Studies found that after age 30, testosterone levels may diminish an average of 2% annually.

Testosterone Physiology

Testosterone is a steroid hormone produced by the Leydig cells of the testes. Its synthesis, like that of many hormones, is the result of a signal-production-negative feedback loop (commonly seen with other hormone synthesis regulation), which uses negative feedback to maintain homeostatic hormone levels. Slide 01

The hypothalamus produces gonadotropin-releasing hormone (GnRH), which passes into the pituitary gland via portal circulation and stimulates the pituitary gland to secrete leutinizing hormone (LH.) LH is released into circulation and reaches the testes, where it acts as the stimulus for testosterone production. As testosterone levels rise, there is an associated negative feedback effect at the hypothatlamus level, which decreases GnRH production. Much like temperature regulating the status of a furnace thermostat, this feedback loop regulates testosterone production. When testosterone levels dip, GnRH synthesis resumes; testosterone levels correspondingly are allowed to rise.   

Testosterone exerts its main effect on cells by affecting DNA transcription. Testosterone can freely enter a cell’s cytoplasm, where it binds to androgen receptor proteins. Once bound, androgen receptor/androgen complexes are formed, which change the androgen receptor’s conformation. The complex enters the cell’s nucleus, where it can bind DNA receptor sites and act as a promoter for specific gene transcription. Testosterone can be converted intra- or extra-cellularly by 5-alpha-reductase, becoming dihydrotestosterone (DHT) and binding the androgen receptor in that form as well. DHT is the more biologically active form of testosterone. Once bound by either molecule, the net effect is protranscriptional and moves a cell toward positive (or anabolic) nitrogen balance and protein synthesis. This effect is not limited to the sex organs; in fact, it plays an important role in maintaining general physiologic function. 

Testosterone’s effects are body wide. Its presence is (or lack thereof) is manifested in multiple organ systems, with testosterone associated with retention of desirable values of actuarial disease risk and with well-maintained body composition. The impact of falling testosterone levels upon many of these parameters is examined as part of this presentation. 

The decline in testosterone levels associated with normal aging is multifactoral, with no one event being the most frequently seen finding in a given patient population. 

There is a decline in the absolute number of Leydig cells in the testes; each remaining cell shows a decline in testosterone production. There is an associated decline in testosterone synthesis proteins and enzymes, evidenced in aging Leydig cells. The net result is the presence of fewer cells, lower production per cell and loss of previous response to stimulatory signals. 

Additionally, the pituitary gland loses the ability to coordinate pulsatile LH secretion patterns and becomes more random. The loss of coordinated LH pulses—rather than a decline in over-all amount of LH production—is associated with diminished testosterone production.   

Another factor affecting the functional availability of testosterone is the age-related increase in sex hormone binding globulin (SHBG). SHBG levels increase with age, regardless of intervention, lowering the amount of unbound (free) testosterone. These proteins "cling" to testosterone. Even though testosterone may be present, it is not "free" or biologically available to do its work. Increasing SHBG levels, therefore, reduces free testosterone to an even greater extent than the reduction seen in total testosterone.  

The previously mentioned factors, acting additively, lead to less total testosterone production, with an increase in binding protein levels, further depressing free/functional testosterone levels.

Signs & Symptoms of Declining Testosterone Levels Slide Slide 08

The signs and symptoms of declining testosterone levels have been examined in validated in two ways: 

  1. Examining an age-matched population cohort, correlating findings within a group.

  2. Following individuals longitudinally, correlating findings to a given subject’s testosterone levels. 

Looking at testosterone levels in these ways creates a valid method to evaluate a patient’s status relative to an age-matched population group and to himself/herself over time.  

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 also are 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 also are associated with increasing levels of leptin. Leptin is a peptide hormone produced by fat cells; 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 age and associated declines in testosterone levels correlate with bone loss in men. Decreased estradiol and testosterone levels are associated with bone loss in women—a phenomenon appearing at an earlier age and more rapidly, compared to men. Up to 30% of men 60 years old and over may become osteoporotic. One in six 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 between age 60 and 80 will show a 50% reduction in her original bone mineral density; one in four will suffer a vertebral or hip fracture. 

  • Decline in sex drive and frequency of sexual thoughts. Interestingly, this decline precedes declines in actual performance. 

  • Increased frequency of erectile dysfunction in men; 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—yet, they are the most often overlooked or incorrectly attributed to stress or "not being as young as you used to be."

  • Decline in stamina and exertional performance. A graph of testosterone and growth hormone diminution can be placed over a graph, reflecting the percentage of professional athletes still performing at a given age and having essentially identical shapes. Similar functional declines also are noted frequently by other "performance-minded" individuals, like business executives and people whose careers demand multi-tasking or complex problem-solving skills.

  • Decline in cognitive skills, concentration and memory. Studies show declining testosterone level is strongly associated with cognitive decline and diminished visuospacial memory.

  • Coronary artery disease and cholesterol derangement. In population studies, low testosterone levels are associated with increased risk of atherosclerotic cardiac disease. Older men treated with testosterone can show decreases in total cholesterol and LDL. Low testosterone levels also are correlated with a greater degree of atherosclerotic obstruction when coronary artery disease is present. 

The first signs of declines in testosterone are generally slightly vague: diminished subjective energy levels, increase in irritability, decline in mood, decline in cognitive performance, loss of early morning erections.  While decreased libido and erectile quality are often the most frequently associated findings associated with falling testosterone levels, they are actually some of the latest symptoms, with other findings present much sooner. 

These symptoms are usually attributed to psychosocial stressors or “aging” and not investigated. As testosterone levels continue to fall, patients notice difficulty with maintaining muscle mass and strength—as well as difficulty handling an increase in body fat, despite a maintained activity level or exercise regime. Meadowlark Lemon once described this situation quite aptly, “I run just as hard as I used to . . . it just takes me longer to get there.” Patients notice lack of progress with dedicated exercise or realize they have to increase subjective workout efforts to maintain their body composition.

Testosterone & Body Composition 

Population studies have pointed out the inverse relationship between both retention of lean mass and gain in fat mass associated with declining testosterone levels. 

The Annewieke study showed a direct correlation between testosterone levels and lean mass in subjects over age 70, with an inverse correlation regarding body fat. (1) Slide 02

The Bross study showed similar findings, but across a much more broad age range. (2)

In addition to correlating testosterone decline with loss of lean mass, studies have been done looking at the relationship between testosterone replacement and a return to a more favorable body composition.  

In two articles by Tenover, testosterone replacement was demonstrated to increase lean body mass. Predictably, subjects who began the studies with the lowest testosterone levels had somewhat greater gains; the group of subjects under age 50 showed greater improvements than older subjects. (3)

The second Tenover study demonstrated that patients with an average testosterone level of 400 ng/Dl (and classically stratified as “normal”) had conformational changes, evidenced after a relatively brief 12-week period of testosterone replacement. (4)

The Urban study showed similar findings, but with a pretreatment testosterone inclusion level of 480 ng/Dl. This study also noted a significant increase in quadriceps and hamstring strength. (5)

Retained muscle mass and strength are strongly associated with decreased fall-and-fracture risks—a finding consistent, even after correcting for bone mineral density. Well-maintained lean mass is associated with better gait and gait correction, resulting in fewer falls and fractures, even in patients with osteoporosis. 

The findings in Snyder’s study were consistent with the aforementioned studies. (6) Slide 03

The consensus from the literature is that testosterone supplementation is accompanied by gains in lean mass, across all age groups. The Snyder and Marin studies demonstrate testosterone supplementation as associated with reduced body fat, with some preferential fat loss seen on the trunk (central). (7)(8) Slide 04  Decline in central body fat is associated with a decrease in waist-hip ratio.  Both central adiposity and waist-hip ratio are independent actuarial risk factors for subsequent development of coronary artery disease.

Testosterone & Bone Mineral Density 

Like the relationship between lean mass, there is a similar correlation between testosterone levels and bone mineral density (BMD). In population studies, like the one published by Annewieke, a direct correlation between BMD and testosterone levels was demonstrated, with retained testosterone levels associated with better-maintained BMD and lower testosterone levels associated with diminished BMD values.

In the Kholsa study, subjects on testosterone replacement therapy showed increase in bone mineral density (BMD) across all age groups (9).

The Snyder study showed an average of 4.2% increase in BMD over a 36-month treatment period. Also, it’s worth noting that average expected bone loss during that same 36-month period would have been approximately 1% per year. After a 36-month study, the treatment group would have shown a greater than 7% improvement, relative to an untreated group. Also of interest, the subjects in the study who had the lowest BMD scores were also the ones who had the largest interval improvements in their BMD. (7) Slide 05

All measures of body composition: lean mass, body fat and bone mineral density; testosterone levels are positively correlated with a compositional advantage, based on reviews of endogenous levels in population studies and longitudinal studies examining outcomes associated with testosterone replacement therapy. Low testosterone demonstrated an association to measures related with higher health risk; intervention reversed these undesirable findings. 

Retained lean mass is associated with increased strength and coordination, maintained physical function and less injury from falls. Body fat reduction is associated with decreased CAD risk and decreased risk for developing adult onset diabetes (DM II) and metabolic syndrome. BMD is associated with decreased risk for osteoporosis, and it has a positive statistical relationship for health risk in general and as a biomarker for dementia risk.

Testosterone & Heart 

When most people think about testosterone, the first organ system that comes to mind is usually the reproductive tract. But, in fact, the heart (myocardium) is the organ with the highest concentration of testosterone receptors. Testosterone should be considered an active participant in cardiac health. 

Testosterone is associated with several effects on cardiac health. It has been linked with reducing coronary artery disease (CAD) and hypertension risks as well as with improving cardiac function in patients with preexisting heart disease. 

In a 1987 study by Chute, this relationship was well-demonstrated, revealing a five-fold reduction in coronary artery disease (CAD) risk in otherwise normal non-hypogonadal community dwelling subjects, whose testosterone levels were in the top quartile vs. those in the lowest quartile. (10) 

And in 1992, Khaw’s prospective study with a 12-year follow-up of 511 men revealed that low testosterone associated with increased central adiposity. (11)

Additional cardiac risk factors demonstrated a relationship to testosterone levels.  

A 1988 study by Khaw showed an inverse correlation between testosterone levels and systolic as well as diastolic blood pressure (BP). His review of 1132 men, ages 30-79, demonstrated that both BP values correlated inversely with testosterone levels. Even in normotensives, higher testosterone levels correlated with lower blood pressure readings and subsequent risk for hypertension development. This relationship was evidenced in all BP ranges and across all age groups in the study. Khaw additionally noted a progressive decrease in blood pressure values for each higher quartile of testosterone level. (12)

Marin, in two studies published in 1992, showed normalization of testosterone levels produced decreases in central adiposity, waist-hip ratio, insulin resistance, total cholesterol and diastolic BP. He described similar associated results in studies on females. (13)  

Marin’s second study showed similar results, repeating his previous findings and additionally showing decreased glucose clearance times after insulin clamping. He concluded that testosterone replacement was associated with improvement in insulin sensitivity. (8) 

Studies by Tenover and Zmuda demonstrate the impact of testosterone on lipid profiles. Slide 06

Published in 1992, the Tenover study revealed results of her treating male subjects (ages 57-76) with intramuscular testosterone replacement therapy. Her data showed increases in lean body mass, depression of urinary hydroxyproline excretion (a marker of bone turnover, elevated when net bone loss is occurring), a significant increase in hematocrit, a decline in total cholesterol as well as low-density lipoprotein cholesterol. Tenover demonstrated that maintained testosterone levels were associated with lower total cholesterol, LDL and risk for CAD diagnosis. (3)

Zmuda, also in 1992, published a 13-year longitudinal study of 41- to 61-year-old men (age at enrollment time). This was a “normal” population sample, having an average total testosterone of 751 ng/Dl at the study’s start and an average decline in testosterone levels over that 13-year period of 41 ng/Dl. The relatively small drop in testosterone was associated with a rise in triglyceride levels and decline in HDL, present after correcting for body habitus and other lifestyle parameters. (14) 

These studies dovetail nicely to illustrate the impact of testosterone on CAD risk and lipid profiles. 

In men with preexisting CAD, testosterone replacement has shown to have clinical efficacy, as well. 

English, KM, 2000, found that men with CAD had lower testosterone levels than age-matched non-CAD subjects. These findings were seen in subjects unaware of any underlying disease and without previous CAD symptoms. The study controlled for any possible change in testosterone levels, which may result from a patient being informed of a diagnosis or potential diagnosis. (15) 

A follow-up study by the same author demonstrated that testosterone replacement therapy in men with CAD was linked to an increased angina threshold during exertion, with accompanying improvement in treadmill performance/endurance vs. baseline and a decrease in the degree of ST depression vs. baseline. Angina profiles improved. Additionally, he found the lower the baseline testosterone, the greater the degree of improvement after therapy. (16) 

In a study published by Wu and Weng in 1993, a group of 62 men with CAD were examined. The group had significantly lower baseline testosterone levels than non-CAD control subjects. After testosterone treatment, the group demonstrated (a) significant improvement in angina symptoms; (b) ST changes during ETT electrocardiography in 68% of subjects; (c) improvement in ambulatory ST segment readings, during Holter monitoring in 75% of the study patients; (d) baseline testosterone levels were inversely associated with the extent of coronary artery occlusion on angiographic imaging at study entry. (17)

In a 1999 study, Webb reported similar findings, with CAD patients showing a 20% prolongation in time to ST segment depression on exercise testing. (18)

Additional studies have served to reinforce these findings.  

1.      By Malkin in the Journal of Endocrinology, points out the association with low testosterone levels and risk for coronary artery disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12967330 

2.      By Bhasin in Clinics of Infectious Disease. The article acknowledges the widespread belief that testosterone supplementation increases the risk of atherosclerosis, but points out actual evidence of this premise is lacking. The author raises the issue that in epidemiologic studies, testosterone levels have been inversely correlated to risk for heart disease and other factors, which predispose to heart disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12942389 

3.      By Eckardstein, published in 2003. The article remains neutral overall, regarding testosterone replacement therapy—finding neither increase nor decrease risk. Of interest is the article’s discussion and description of why negative articles on testosterone looking only at HDL miss important points, regarding cardiac risk. In this case, no associated risk is also a positive outcome when looking at testosterone therapy; no harm is a fine result.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12914731 

4.      By Sieminska, published in 2003. The work found that men with coronary artery disease had significantly lower levels of free testosterone than men without CAD.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12761451 

5.      By Barud, published in 2002. The article showed a significant inverse correlation between testosterone level and antibodies to oxidized LDL—and that only testosterone levels were associated with lowering this risk factor for heart disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12204799 

6.      By Wassef, published in 1998. The work points out that only a few items affect Lipoprotein (a) in a positive fashion. Lipoprotein (a) is a significant heart disease risk factor. The author states that niacin compounds, moderate doses of alcohol, neomycin and androgens are associated with lowering Lp(a).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10665339 

7.      By Zhao in the 1998 International Journal of Cardiology. Zhao found that testosterone levels in patients with heart disease were significantly lower than in healthy subjects, noting that statistically, low total testosterone levels are associated with increased risk for diagnosis of heart disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9510490 

8.      By Phillips, published in 1994. The article reveals testosterone levels correlated negatively with risk factors for heart disease, including Fibrinogen, Plasminogen, Activator Inhibitor 1 and insulin; it concluded that in men, low testosterone levels might be a risk factor for heart disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8172848 

9.      By Contoreggi, published in 1990. Another neutral study finds no significant differences in testosterone, when comparing groups of men with and without heart disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2147671 

10.  By Sewdarsen, in Atherosclerosis, 1990. In their total male patient population having had myocardial infarction (heart attacks) between ages 30-60, it was found that their testosterone concentration was significantly lower than in men without a cardiac history.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2242091 

11.  By Srzednicki, published in 1990. It was found that testosterone concentrations in unstable coronary artery disease were significantly lower than in men with stable coronary artery disease—and lower still than those found in healthy controls. Again, this points out an inverse correlation between testosterone and coronary artery disease risk.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2287567 

12.  By Sewdarsen, published in Atherosclerosis, 1986. It was concluded that low testosterone levels were a statistical risk factor for future myocardial infarction.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3729798 

The Muller, M. et al study was a landmark meta-analysis of the relationship between testosterone and subsequent risk for cardiovascular disease. While there had been some conflicting data in previous observational studies, Muller’s group analyzed the data from studies, which included adjustments for concurrent risk factors so testosterone was the only identifiable difference between otherwise matched groups.(19)

http://www.J Clin Endocrinol Metab. 2003 Nov;88(11):5076-86.

Their review included 8,150 men from 11 studies. The data analysis revealed that in 10 of 11 studies, higher testosterone levels were associated with lower cardiovascular disease risk (including aortic and carotid disease). Men in the upper third for testosterone level were at one-fifth the atherosclerosis risk for that of men in the lower one-third.  

In this graphic summary, the 66 percentile values are marked, showing a corresponding reduction in relative risk vs. average testosterone values. (19) Slide 07

A follow-up study of 400 subjects by the same author was published in 2005. Muller concluded: “Higher testosterone and SHBG levels in aging males are independently associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, independent of insulin-levels and body composition measurements, suggesting that these hormones may protect against the development of metabolic syndrome.” (20)

Testosterone & Brain

In the film “Sleeper,” Woody Allen described the brain as his second favorite organ, and the same can be said of testosterone’s favorite organs. The brain is second only to the heart in terms of abundance of testosterone receptors and receptor concentration. Testosterone features prominently in neurologic literature; it is associated with maintained cognitive function in the aging brain, lowered dementia risk and improvements in the neurophysiology of subjects with preexisting dementia. 

Rupprecht, in Trends in Neuroscience, 2003, discusses the novel physiologic effects of testosterone on neuronal receptors and receptor metabolism regulation. This study reviewed testosterone’s neurocognitive importance and its possible role in decreasing symptoms of depression, anxiety and panic disorders. (21) 

Moffat, et al, showed that AD risk is inversely associated with Free Testosterone Index (FTI)—this association remained after adjustments for age, education, smoking status, body mass index, diabetes, any cancer diagnoses and hormone supplement history.  Increases in FTI associated with decreased risk of AD (hazard ratio = 0.74; 95% CI = 0.57 to 0.96)—a 26% decrease for each 10-nmol/nmol FTI increase. (22) 

Additionally, Moffatt demonstrated that free testosterone concentrations were lower in men who subsequently developed Alzheimer disease. Interestingly, these findings were present before any symptom of AD was present, either by patient history or clinical exam. The study was of excellent length with a mean follow-up time of 19 years, with some patients followed for 37 years.  (22)

Gouras GK, et al. They demonstrated that testosterone reduces neuronal secretion of Alzheimer’s β-amyloid peptides. (23) 

Papasozomenos demonstrated that testosterone decreases the change of Tao protein phosphorilation seen in AD plaques. (24) 

Gillett, in 2003, demonstrated that lower androgen levels are associated with increased plasma levels of Amyloid beta peptide 40 in older men with memory loss or dementia, suggesting a sub-clinical androgen deficiency enhances the expression of Alzheimer's disease-related peptides in vivo. (25)

Tan, in 2003, conducted a study, which showed testosterone modulation in men with AD was associated with significant improvement on MMSE and other cognitive measures, while the placebo group demonstrated a typical decline in cognitive status. (26)

Hogervorst, 2003: Patients with the APO-E4 allele are at high risk for development of future AD and have been shown to demonstrate a concurrent decrease in testosterone compared to normal controls, even in the absence of any other demonstrable finding. (27) 

Another article by the same author in 2004 discusses the direct predictive relationship between testosterone levels and AD risk. (28)

Paoletti, 2004: In male and female subjects, lower testosterone levels were evidenced in AD patients vs. controls. Elevated SHBG also demonstrated a positive association; testosterone therapy was associated with lowered SHBG. Lower androgen indices in both men and women were associated with AD. (29) 

In all, maintained testosterone levels carry a significant cognitive benefit.

Testosterone, Erectile Function & Libido

The effects of testosterone on erectile function and libido have been well-documented for the treatment of “classically” hypogonadal men.  

The Kwan and Skakkeback studies show improvement on several sexual performance fronts, as expected. (31)(32) 

The Hajjar, O’Carroll and Morales studies demonstrate the same benefits in subjects who did not meet diagnostic criteria for frank hypogonadism. These subjects noted improvement in libido and performance with statistically normal range testosterone levels. (30)(33)(34) 

Carani and Jain performed studies on men with normal pretreatment testosterone levels who presented erectile dysfunction with positive results in both studies. (35)(36)

Testosterone & Mood

Looking at testosterone and its relation to measures of mood or well-being, Marin demonstrated improvement in mood scores with testosterone supplementation. (13) 

Cooper published similar findings with regard to anxiety score (37); Margolese noted that lower testosterone levels were correlated with the diagnosis of depression. (38)

In studies of sexual function, mood and well-being, testosterone levels and supplementation correlate with improved quality of life.

Testosterone & Prostate Cancer Risk 

At some point in most physicians’ training, they must have met the same spectral urologist, who traveled from training program to training program, walking the hallways proclaiming testosterone is associated with prostate cancer risk. These same physicians-in-training must have been hypnotized by this urologist and his post-hypnotic suggestion—never go to the literature and look the topic up. On one level, the mythical urologist was correct: Testosterone is associated with prostate cancer risk, but in the exact opposite relationship he proclaimed.  

The following list reflects a review of testosterone and prostate cancer risk. There is a repeated lack of association between testosterone and cancer risk, with studies either yielding a null result or demonstrating an inverse relationship between testosterone and prostate cancer risk. 

1.      Published by Cooper in the Journal of Urology. Study showed that testosterone replacement therapy was not associated with any rise in PSA or prostate volume. (37)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9649259 

2.      By Hoffman in the Journal of Urology in 2000. Hoffman reported that patients with prostate cancer and low free testosterone had more extensive disease. In addition, all men with a biopsy Gleason score of 8 or greater had a low serum free testosterone. His conclusion was that low testosterone levels might be a marker for aggressive prostate disease. (41)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10687985 

3.      Asbell in the Journal of the National Medical Association found no correlation between PSA and androgen levels in a study of prostate cancer patients. (42)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11052458 

4.      Published by Rhoden in the New England Journal of Medicine in 2004, a comprehensive review of 72 prior studies concluded there was no evidence supporting a causal link between testosterone replacement therapy and an increase in prostate cancer risk. The following link will be directed to the literature citation. The full article is available via the NEJM. (43)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14749457 

5.      Carter in the Journal Prostate in 1995. Carter found no correlation between testosterone and prostate cancer risk in patients, followed as long as 15 years before any diagnosis of prostate pathology was noted. His concluded that his data demonstrated that no measurable difference exists in testosterone levels among men who are destined to develop prostate cancer in those without disease. (44)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7541528 

6.      Heikkila in Cancer 1999. Heikkila also reached the same conclusion.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10421267 

7.      Gustafsson in the British Journal of Urology. Again, the study failed to demonstrate a connection between testosterone levels and prostate cancer risk.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8814852 

8.      Zhang in the Journal Prostate, published in 2002. Zhand found that patients with prostate cancer were found to have low androgen levels.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12386917 

9.      Massengill published in the May 2003 Journal of Urology. The study revealed that low testosterone levels were predictive of pathological stage in patients with prostate cancer.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12686805 

10.  Rhoden, also in the Journal of Urology in December 2003, evaluated patients with prostatic intraepithelial neoplasia—commonly regarded as a pre-malignant change in the prostate—and showed no change in PSA or their tissue status when given testosterone replacement therapy over a one-year period.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14634413  

11.  Chen in the Journal of Cancer Epidemiology Biomarkers and Prevention. Chen found that testosterone levels were unrelated to prostate pathology.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14693730 

12.  Hoffman in the Journal of Urology in 2000. Again, the study found that low testosterone levels, rather than high, were a marker of prostate disease. (41)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10687985 

13.  Stattin in the International Journal of Cancer did a pool-to-prospective study and found there was no evidence to conclude a connection exists between high testosterone levels and increased prostate cancer risk.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14648709 

14.  Gann in the Journal of the National Cancer Institute in 1996. Gann found it was not testosterone levels that related to prostate cancer risk, but rather low levels of Sex Hormone-Binding Globulin in conjunction with high testosterone levels.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8757191 

15.  Hsing in the Journal of the National Cancer Institute in 2003. The study revealed a connection between insulin-resistance and the effect of high insulin levels on prostate cancer risk being a positive association.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12509402

 

16.  Slater, S. Drugs and Aging, 2000. After 34 studies were reviewed, no data existed to support higher risk for prostate CA with elevated testosterone levels vs. controls.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11200304   

17. Zhang, Prostate, 2002. The work also reported that in patients with prostate cancer, testosterone levels were lower than in controls.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12386917  

18. Gustafsson, Br J Uro, 1996. The study demonstrated an inverse relationship between dihydrotestosterone levels and the presence of prostate cancer.  His study also demonstrated further inverse correlation between DHT and tumor stage.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8814852

 19.  Haapiainen, 1988. The study revealed higher pretreatment testosterone levels in subjects with prostate cancer were associated with better survival. 

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt= Abstract&list_uids=3187401

Lab Tests: Testosterone Levels

In making the decision regarding which tests to use for assessing a patient’s testosterone levels, two tests have the greatest clinical utility. Total testosterone and free testosterone provide ample information for appropriate decision making. 

Total testosterone measures all forms of testosterone in a sample, including protein bound and hormone, which is bound to sex hormone binding globulin (SHBG). 

Free testosterone measures hormone that is unbound and actively bioavailable. 

While free testosterone levels have the most utility, measuring total testosterone as well provides additional information for safety monitoring and epidemiologic data. 

There are indices based on calculations using total testosterone and other laboratory values: bioavailable testosterone and free androgen index. These calculations have become much less clinically important, given the availability of free testosterone levels. 

Measuring sex hormone binding globulin (SHBG) does not provide any additional information, which would alter the clinician’s decision whether or not to institute therapy or alter dosage algorithm. It is interesting to note that regardless of intervention, SHBG levels continue to rise with age. 

This table demonstrates normal range testosterone levels by decade of life. (51) Slide 08  

The current laboratory custom of providing testosterone results normed to all men (age 20-70) lacks adequate precision, regarding the assessment of a patient’s testosterone levels relative to an appropriately precise age-matched cohort. 

Of note, these are testosterone levels relatively well preserved over time, with the 66th percentile value to age 100 still being above 500 ng/dl. 

These values offer a glimpse at what values are statistically associated with best clinical status and lowest health risk at given age intervals. 

The 66th percentile values are provided because of their correlation to literature reports of reduced disease risks; 33rd percentile values are provided on the same basis with regard to elevation of health risk.

Testosterone Supplementation

Therapy goals are based on the preceding table and the literature, citing the lowest health risk values. 

Testosterone supplementation should take place within a comprehensive milieu, which allows optimizing any opportunity to identify and address underlying pathology as well as to avoid any mis-association of pretreatment disease and patient status after treatment. 

The establishment of baseline laboratory parameters allows for the most efficient therapeutic choices and makes subsequent evaluation relevant in a specific context for each individual. 

Prostate Specific Antigen (PSA) measurement must accompany testosterone levels at the time of an initial evaluation to screen for any preexisting prostate disease, direct any prerequisite work-up of elevated level associated with prostate disease and use as a baseline for future program follow-up.

Other studies—such as thyroid hormones, growth hormone (hGH), leutinizing hormone (LH), dehydroepiandrosterone (DHEA), blood count, lipid profiles and other laboratory and metabolic markers (body composition and bone density)—play roles in maximizing a Testosterone Replacement Program. 

Follow-up evaluation over time is required to avoid sub-therapeutic or supraphsyiologic hormone levels—and to maximize benefit while minimizing any potential side effect.

Delivery Mode

After the decision to augment testosterone levels has been made, the next step is deciding on the proper means of delivery. There are several different modes of testosterone delivery, but the best method varies from individual to individual and is dependent upon several factors. Optimally, a testosterone delivery method should be clinically effective in correcting the signs and symptoms of testosterone decline and produce predictable, reproducible physiologic levels of testosterone. 

Testosterone is available directly in oral, injectable, topical and implantable formulations. It may also be supplemented indirectly by human chorionic gonadotropin administration, which stimulates testosterone production by the testes. 

An illustration of the testosterone synthesis pathway: Slide 09

Of note, administration of “precursor” molecules occurring higher in the synthesis pathway is not typically associated with meaningful downstream alterations in testosterone production. 

A recap of the testosterone feedback pathway, with an addition: Slide 10

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 raising testosterone levels may concomitantly raise estradiol levels in an undesired fashion. Estradiol can act as a testosterone antagonist and negatively impact the clinical response to testosterone replacement therapy. 

When choosing a method of testosterone modulation delivery, we are faced with several possible paths. 

In an ideal world, there would be a safe and effective oral product—as oral medication use is associated with the highest patient compliance. At present, there is no adequate product. Testosterone delivered orally undergoes first-pass metabolism, rendering it difficult to achieve useful serum levels. Additionally, much of the oral dose is converted into circulating dihydrotestosterone (DHT), creating supraphysiologic levels of DHT.  

Using current oral preparations would also dictate TID or even six-times/per-day dosing—and is associated with potential hepatotoxicity.   

Androgens (such as fluoxynesterone, methyltestosterone, oxandrolone or danazol) are available for clinical use, but are not appropriate for long-term testosterone replacement therapy. Their use is specific for certain disorders and must be used with great caution since they can cause an increase in liver enzymes, blockage of liver drainage pathways, direct liver damage and even liver tumors. They also dramatically raise serum LDL cholesterol, decrease HDL cholesterol and have been associated with increased risk of myocardial infarction and stroke. Testosterone undecanoate is a testosterone compound given in an oral base, taken up by the lymph ducts in the intestines; it can bypass the liver, thus minimizing the typical side effects. It has, however, an extremely short half-life, has low (and frequently unpredictable) bioavailability from dose to dose; and is not currently approved by the FDA for use in America. At present, there are no recommended oral testosterone formulations.  (46)

Testosterone formulations are also available for topical placement. These formulations allow testosterone absorption through the skin—the therapy of choice for raising testosterone levels in women. In our experience, there is only limited application for this delivery system in men because its produces supraphysiologic serum levels of DHT: Testosterone is absorbed through the skin; 5 alpha-reductase converts much of the testosterone to DHT, raising circulating levels of DHT and increasing the exposure of prostate and hair follicle cells to DHT rather than testosterone, which is not as active in these cells and not as well taken up. Testosterone patches have also been associated with other minor disadvantages, including low obtainable maximum serum testosterone levels, difficulties with the skin area needed to apply creams for 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 studies have shown to produce a 30% - 50% failure rate, due to intolerance in clinical applications. The quite small amounts of testosterone crème required to raise testosterone levels in women have not been associated with these problems. Patches may seem more user friendly compared to injections, but we have found their use limited due to the above concerns. Slide 11

The current standard bearer for direct testosterone supplementation is intramuscular (IM) delivery. Depot formulations of testosterone exist (suspended in oil), giving predictable absorption patterns. Excess conversion to DHT does not occur; at a dosing interval of one week, there is a well-maintained sinusoidal pattern to testosterone levels.

Testosterone Dosing 

The typical starting dose is 1mg/Kg body weight per week. 

At dosage intervals of greater than one week, supraphysiologic peaks would be required to maintain an adequate testosterone trough level between doses.  

Once-monthly dosing is also associated with longer sub-therapeutic trough times before the following injection. 

Another item of concern associated with larger testosterone doses at longer intervals: Testosterone peak levels are an important determiner of estradiol levels. The higher the peak level of testosterone, the greater the associated rate of conversion to estradiol. Since estradiol is known to mitigate the effects of testosterone and diminish clinical responses to therapy in the face of well-maintained testosterone levels, this potential result should be minimized. Maintain lower testosterone peaks by delivering testosterone at a weekly dosage interval. Slide 12

Given that a significant contribution to declining testosterone levels can be associated with decreases in pituitary production of LH and loss of coordination of LH release, it is possible to affect testosterone levels by attempting to simulate previous LH secretion patterns with an LH analog: Human Chorionic Gonadotropin (HCG). 

Human Chorionic Gonadotropin (HCG) contains a sub-unit that is homologous to LH, providing an alternative to simple testosterone replacement, which allows a clinician to utilize the patient’s own testicular function to favorably alter testosterone levels.

HCG can be delivered as a subcutaneous pulse dose that mimics lost pituitary physiology, which may be sufficient to stimulate the testicles and allow return of previous testosterone levels without requiring any direct testosterone replacement. 

With advancing age, HCG responsiveness declines, from 95% response rate at age 40 to approximately 50% at age 65. This change in responsiveness occurs independently of any intervention. Therefore, over time, HCG therapy can show a decline in effectiveness along this curve. Slide 13

When making a decision whether or not to use HCG therapy, LH levels may be useful. Elevated LH levels would predict a low likelihood of success (“beating a dead horse” ever harder still yields the same outcome) while normal or low LH levels offer a more likely prediction for HCG success. Slide 14

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