Understanding Testosterone Replacement Therapy
by Monica Mollica
Testosterone Replacement Therapy (TRT) in Testosterone Deficient men – effects on fat loss, waist reduction and metabolic syndrome components
Testosterone deficiency in men, aka hypogonadism, is associated with increased total and abdominal fat mass, and reduced muscle mass, which negatively impacts body composition.[1, 2] This contributes to development of risk factors like insulin resistance, chronic inflammation, and atherogenic dyslipidemia (a triad of increased blood levels of small, dense LDL particles and triglycerides, and decreased levels of HDL particles), which increase the risk for cardiovascular disease, metabolic syndrome and diabetes.[1, 3-16]
Previous studies have shown that testosterone replacement therapy ameliorates these risk factors in testosterone deficient (hypogonadal) men; it increases insulin sensitivity [17-20] and HDL (the “good” cholesterol)[9, 10, 20, 21], and reduces waist circumference [9, 20, 22], fasting blood glucose [9, 20] triglycerides (blood fats), LDL (the “bad” cholesterol) [19, 22-24], and several inflammatory markers.[17, 25]
A 2011 meta-analysis concluded that testosterone replacement therapy improves metabolic control, as well as reduces abdominal obesity. Many studies have shown that testosterone replacement therapy in hypogonadal men increases muscle mass and reduces fat mass.[19, 26-32] Further, adding testosterone (50 mg/day for 1 year, administered as a transdermal gel) to a diet and exercise program results in greater therapeutic improvements of glycemic control and reverses the metabolic syndrome.
Testosterone also has direct (non-obesity mediated) beneficial effects on many metabolic and cardiovascular risk factors [12, 33-37], and reduces death risk independently of body fat status. In line with all these effects, low testosterone levels are associated with increased risk of cardiovascular complications , and all-cause and cardiovascular disease death [40-42]. Low testosterone may thus be a predictive marker for men at high risk of cardiovascular disease. In a group of men aged 50-91 who were followed for 20 years, it was found that men whose total testosterone levels were in the lowest quartile (241 ng/dl or lower) were 40% more likely to die than those with higher levels, independent of age, adiposity, lifestyle or presence of cardiovascular risk factors.
Thus, treatment of testosterone deficient men with testosterone has demonstrated considerable health benefits. Despite this, critics state that most of the studies on testosterone replacement therapy were too small. They also argue that the studies were of too short duration (most of them lasting 6-12 months), and that the long-term effects of testosterone on body composition are not known.
Two 5 year long studies were just published that addressed the duration and small study size shortcomings in previous research…
Effect of testosterone replacement therapy on body fat and waist circumference
This was a registry study of 255 men, aged between 33 and 69 years (mean age 58), who had sought consultation in an urologist’s office for various medical conditions, e.g. erectile dysfunction, decreased libido, questions about their testosterone status or a variety of urological complaints. 
Upon clinical and laboratory investigation, the subjects were found to have subnormal total testosterone levels, mean 223 ng/dl. All men received treatment with testosterone undecanoate injection (a long acting form of testosterone [44, 45]) at a dose of 1000 mg administered at baseline and 6 weeks and thereafter every 12 weeks for up to 5 years (60 months). Body weight and waist circumference were measured at baseline and yearly.
testosterone-replacement-therapy-men* The testosterone treatment resulted in a significant increase in total testosterone levels, which increased from a baseline level of 223 ng/dl to 467 ng/dl within the first 12 months, and thereafter stabilized between 519-548 ng/dl for the remainder of the observation period.
* Waist circumference declined from 42.4 in (107.7 cm) to 39 in (99 cm), with a mean reduction of 3.7 in (9.4 cm). The reduction in waist circumference was significant at the end of each year compared to the previous year over the full 5-year observation period.
* Body weight decreased from 221 lb (100.1 kg) to 204 lb (92.5 kg), with a mean loss of 24.5 lb (11.1 kg).
As for the waist circumference reductions, the weight loss was significant at the end of each year compared with the previous year over the full 5-year observation period.
* Of 261 patients treated with testosterone for 5 years, only 6 patients (2.3 %) got diagnosed with prostate cancer.
Effect of testosterone replacement therapy on metabolic syndrome components
The same research group performed another study investigating the effects of the same 5 year long
testosterone replacement therapy on metabolic syndrome components . In this study, the testosterone deficient (hypogonadal) men had baseline total testosterone levels of 286 ng/dl (mean value), range 170-350 ng/dl. As in the above mentioned study, all men received treatment with testosterone undecanoate injection, 1000 mg administered at baseline and 6 weeks and thereafter every 12 weeks for up to 5 years (60 months). Blood lipids, glucose, liver enzymes and haemoglobin A1c (HbA1c) were measured at baseline and yearly.
* The testosterone treatment resulted in a marked and significant gradual decrease in LDL “bad” cholesterol levels from approximately 164 mg/dl (4.2 mmol/L) to approximately 110 mg/dl (2.8 mmol/L).
The reduction in LDL level was significant within the first year of treatment and remained low over the course of 5-year treatment period.
* HDL “good” cholesterol levels increased slightly but significantly and remained elevated over the 5-year period of treatment. The increase was gradual and significant within the first year of treatment.
* The total cholesterol/HDL ratio, which gives an indication of cardiovascular disease risk [47, 48], improved considerably from 5.44 to 3.49, suggesting a favorable change in the lipid profile and a potential reduction in cardiovascular disease risk.
testosterone-replacement-therapy-men-cardiovascular-effects* Triglyceride levels decreased from 276 mg/dl (3.1 mmol/L) to 190 mg/dl (2.2 mmol/L), and remained low throughout the 5-year treatment period. The reduction in triglyceride level was significant within the first year of treatment and remained low over the course of 5-year treatment period.
* Systolic blood pressure was reduced from about 154 to 138 mmHg and diastolic blood pressure was reduced from 93 to 80 mmHg. The decreases in blood pressure were significant and gradual over the first 2 years and remained low over the entire course of the 5 years of treatment.
* Fasting blood glucose dropped from 103.4 mg/dl (5.74 mmol/L) to 97.6 mg/dl (5.74 mmol/L). The decrease was significant after 12 months and further declined after 24 months and then reached a plateau.
* The decrease in fasting blood glucose was paralleled by a marked decrease in glycated hemoglobin (HbA1c), from 7.06 % to 6.16%. In contrast to fasting glucose, the decrease in HbA1c was statistically significant after 12 months, between 24 and 12 months, between 36 and 24 months, between 48 and 36 months, and between 60 and 48 months.
* The inflammatory marker CRP was markedly and significant decreased from 6.29 to 1.03 U/L), with a plateau after 36 months.
* The liver enzymes aspartate transaminase (AST) dropped from 43 to 20 U/L) , with a plateau after 24 months), and alanine transaminase (ALT) from 44 to 21 U/l , with a plateau after 36 months).
* Prostate volume increased from 28.51 ml to 30.04 ml, reaching a plateau after 3 years. PSA (prostate specific antigen increased from 1.77 to 1.83 ng/ml, with a plateau after 2 years. There were no occurrences of urinary retention or other problems related to benign prostatic hyperplasia (BPH). Only 3 patients were diagnosed with prostate cancer. This represents an incidence of 1.2% (3 patients out of 255).
These two studies provide compelling data on the benefits and safety of testosterone replacement therapy, and confirm the results of previous smaller and shorter duration studies.
The 1.2-2.3% incidence of prostate cancer in these studies is far lower than the 9.6% incidence reported in the general population. Another 5 year long safety study has also found that testosterone treatment didn’t change neither the Prostate Symptom Score (IPSS), post-void residual (PVR) volume, maximum urinary flow (Qmax) rate nor prostate size in obese testosterone deficient men with metabolic syndrome and moderate lower urinary tract symptoms at baseline. Additional support for prostate safety with testosterone replacement therapy comes from meta-analysis of 19 studies, which revealed no greater risk of prostate cancer in men with testosterone deficiency who received testosterone therapy versus men who received placebo. Another 6-year long study confirmed the prostate safety of testosterone replacement therapy. Further, a large international study comprising 3886 men with prostate cancer and 6438 age-matched controls found no associations between prostate cancer risk and blood levels of total testosterone, free testosterone, or dihydrotestosterone.[53, 54] In the to date largest worldwide sample of hypogonadal men, testosterone replacement was found to be safe, effective and well tolerated.
As I discussed in a previous article “Testosterone Replacement Therapy – why is it so controversial?“ , there is no compelling evidence that testosterone is the driving factor in the development or progression of prostate cancer. Evidence accumulated over the last 15 years strongly indicates that beyond the near-castrate range there is little, if any impact of changes in testosterone levels on prostate cancer growth.
It should be noted that the baseline total testosterone levels is these two studies were in the low normal range, and that testosterone dose was low and given over an extended period of time. Also, the final level of 520-550 ng/dl is still probably suboptimal for most men.
testosterone-replacement-therapy-men2Although there is no consensus as to what is a desirable range of testosterone, clinical data suggest that the normal range of testosterone in adult men is between 346-1154 ng/dl (12-40 nmol/L). A threshold of 349 ng/dl (12.1 nmol/L) representing the lower end of the normal range was confirmed in an analysis of a number of well-known studies such as Framingham Heart Study generations 2 and 3, European Male Aging Study and the Osteoporotic Fractures in Men Study. The large normal reference range of testosterone levels in adult men underscores the importance of contrasting the low end with the high end.
This was illustrated in a study showing that testosterone levels have to exceed 550 ng/dl in order to cut cardiovascular disease risk. Also, triglyceride levels can respond differently in the low end vs. high end of the normal reference range. Additionally, both supplementation dose and age will influence the outcomes.[12, 61] I will cover this more in-depth in an upcoming article.
Studies on the effect of testosterone on HDL have been inconsistent, showing increase [10, 21], decrease [62-66] or no changes [22-24, 26] in HDL levels in testosterone deficient med treated with testosterone. One analysis showed, counter intuitively, that larger doses of testosterone were associated with smaller declines in HDL. These discrepancies in the various studies may relate to use of varying formulations of testosterone, dosage administered, duration of the studies, co-morbidities of subjects enrolled in the various studies. The decrease in HDL in response to testosterone supplementation was seen mostly in studies with supra-physiological testosterone doses.[28, 67, 68] Recently studies have shed light on the importance of HDL quality and function, as opposed to just HDL levels (quantity) , which is the commonly measured HDL parameter. Accumulating data is showing that testosterone beneficially might affect several aspects of HDL composition and functionality [69-71]. The link between testosterone levels and HDL quality and quantity is subject of intense research and debate, which I will go over in an upcoming article.
Triglycerides (blood fats) and the triglyceride/HDL ratio – LDL particle size and Insulin Resistance
Another interesting finding in the second of the above outlined studies is the marked reduction in triglyceride levels. This will lower the triglyceride/HDL ratio (especially when combined with an HDL elevation), which in turn reduces insulin resistance and increases LDL particle size.
An increased LDL particle size indicates an improvement of atherogenic dyslipidemia, and can convert a person from the dangerous “pattern B” to the healthier “pattern A”. For more on the LDL particle size and patterns A and B, check out my previous article “Blood Cholesterol Testing – don’t let the simple numbers fool you!”
A decreased triglyceride/HDL ratio also indicates improved insulin sensitivity [72-76]. Thus the reduction in triglyceride/HDL ratio seen in the 5-year long testosterone replacement study  confirms previous research showing that testosterone improves insulin sensitivity. [17, 18]
Total cholesterol/HDL ratio
The total cholesterol/HDL ratio (like the just mentioned triglyceride/HDL ratio) gives an indication of cardiovascular disease risk [47, 48]. A decrease in the total cholesterol/HDL ratio from 5.44 to 3.49 with testosterone therapy  therefore indicates improvement in another aspect of the blood lipid profile, and a reduction in cardiovascular disease risk.
In the long-term studies outlined in this article [43, 46], subjects were told to keep their habitual lifestyle, so the results are not due to any major other intervention. The remarkable effects of testosterone replacement therapy seen in these two studies, even at low dosages, shows how powerful testosterone therapy can be, and how greatly it can contribute to combat expanding waistlines, obesity, metabolic syndrome, cardiovascular disease and diabetes.
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