Table of Content
- Why is testosterone replacement therapy required?
- Diagnosis of hypogonadism / low testosterone level
- Treatment of hypogonadism
- Benefits of testosterone replacement therapy
- Side effects of testosterone replacement therapy
- Prostrate related side effects of Testosterone Replacement Therapy
- Prostate problems
- Liver problems
- Polycythemia risk
- Other effects of TRT
- Future prospects of TRT
Why is Testosterone Replacement Therapy Required?
In a nutshell: male hypogonadism. This medical condition is characterized by a reduction in testosterone serum levels which leads to decreased sex drive, decreased ejaculate volume, erectile dysfunction, weakness, loss of body/facial hair, reduced bone density, increased body fat, reduction in lean body mass, anemia and fatigue.
This condition is often overlooked or ignored by men as they grow old – they attribute the symptoms to aging itself rather than accepting the fact that aging has caused the onset of hypogonadism which has led to the adverse symptoms. A study conducted of 2162 middle-aged (45+ years) men who visited primary care practices in the US was conducted to observe the prevalence of the condition – 836 were hypogonadal – which implied a crude prevalence ratio of about 38.7%.
|Characteristic||Hypogonadal patients (n =836)||Eugonadal patients (n = 1326)||p-value||Total patients (n = 2165)|
|Race, n (%)||–||–||p-value||–|
|White||700 (83.7)||1077 (81.2)||–||1780 (82.2)|
|Hispanic||15 (1.8)||42 (3.2)||–||57 (2.6)|
|Asian||2 (0.2)||11 (0.8)||–||13 (0.6)|
|Other||5 (0.6)||16 (1.2)||–||21 (1.0)|
|Mean age, years (SD)||61.6 (10.57)||59.9 (10.11)||0.0003||60.5 (10.33)|
|Mean BMI, kg/m2(SD)||31.5 (6.06)||28.5 (5.04)||<0.0001||29.7 (5.64)|
Diagnosis of Hypogonadism / Low Testosterone Level
At this time, the diagnosis of hypogonadism requires the identification of specific signs and symptoms that point to a deficiency of testosterone. The most common symptom hypogonadism is low sex drive i.e. libido.
Other signs include decrease bone strength and muscle mass, erectile dysfunction, increased body fat, breast discomfort, gynecomastia, mild anemia, sleep disturbance, loss of hair on face and body, hot flushes, reduced vitality, and compromised mental capability i.e. lowered concentration, fatigue and depression.
The issue with these symptoms is that they are not exclusive to low serum testosterone levels – they can imply other conditions that manifest as men age.
Questionnaires are not recommended for testosterone level testing; the best way is a laboratory diagnosis which involves a meticulous biochemical and physical workup. For additional accuracy of results, transient reductions in testosterone levels which can occur due to illnesses; are ruled out through careful clinical checkups and regular hormone measurement.
Hypogonadism, which can be either primary or secondary, has risk factors in older man that include chronic illnesses such as chronic obstructive lung disease, diabetes mellitus and renal, inflammatory arthritic, and HIV related conditions; obesity; hemochromatosis and metabolic syndrome which should be identified and treated in a timely manner.
Treatment of Hypogonadism
The solution for hypogonadism i.e. reduced testosterone levels lies in a treatment known as testosterone replacement therapy that restores natural hormone levels in young adults and theoretically, imitates the natural production of the hormone ensuring that testosterone levels are maintained without any considerable side effects.
An even more crucial property of TRT is that it reduces the apparent symptoms of hormone deficiency. The overall objective of this therapy is to restore the quality of life and enhance the vitality of the subject.
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There are several different delivery mechanisms for boosting testosterone; including testosterone supplements, tablets, transdermal systems, injections, pellets, orathe l and buccal preparations of the hormone. The method of delivery should be decided after informed discussion between the physician and the patients. Short-acting mechanisms are preferred over long-term ones for the initial treatment of patients. The optimal hormone level enhancement by TRT, for young adult males, should be in the mid-range but older men may require a higher dose to enjoy the proper benefits.
Oral agents, such as testosterone undecanoate, which is absorbed mainly via the lymphatic system, is used quite commonly in the US and is the safest supplement as well. However, there have been rare occurrences where the use of this supplement caused an elevation in testosterone levels beyond the middle range.
Intramuscular agents – previously, testosterone enanthate and cypionate were delivered via intramuscular injection (with 2-3 week intervals) that caused sharp peaks and troughs in testosterone levels leading to alternating symptomatic benefits and a subsequent return to base line conditions. In spite of this, these two hormones were preferred by san everal males over others. An excellent long term alternative to this ‘radical’ method is injection of testosterone undecanoate after intervals of up to 3 months.
Transdermal systems – this method of delivery is available either as a scrotal/non-scrotal skin patch or as a gel preparation. One application of this mechanism can lead to approximately normal circulating testosterone levels for 24 hours – obviously, it needs daily application to remain effective. This method has been linked to skin irritation, but not in the case of the gel preparations. The most widely used gel preparations of the hormone, in the US, are Testim® and Androgel®.
Sublingual and buccal – A cyclodextrin shell releases testosterone after a sublingual formulation of cyclodextrin-complexed testosterone is quickly taken into circulation. This method is believed to possess considerable therapeutic potential to yield physiologic testosterone levels.
A buccal tablet e.g. Striant®, that delivers 30 mg of the hormone, can be applied daily, above the lateral incisors, to the upper region of the gum. The daily applications should be around 12 hours from each other.
This is a fast acting method that restores testosterone levels to healthy values within just 4 hours of application, with stable levels attained within 24 hours of twice-a-day dosing and achievement of normal range of testosterone concentration. The only drawback is the difficulty in keeping up the oral buccal treatment.
Subdermal implants offer the longest term solution with extended zero-order, steady state delivery properties that last for 4 – 7 months. Four 200 milligram pellets i.e. 800 mg net dose, is implanted below the skin after every 5 – 7 months. There is a 5-10% infection risk in this testosterone supplementation procedure at the site of implantation and during removal of depleted pellets, and their testosterone release rate has not been thoroughly studied yet.
Benefits of Testosterone Replacement Therapy
Enhancement in Sexual Function
A deficiency or reduced levels of biological testosterone is a major culprit for the decline of sexual function with age in men according to the International Index of Erectile Function’s questionnaire. Those males who suffer from reduced sex drive or erectile dysfunction can be treated with testosterone replacement therapy.
Sufficient supplementation of testosterone has a restorative effect on the venous leakage which occurs in the corpus cavernosum – a common etiological factor in erectile dysfunction occurring in older men.
Long term follow up studies of hypgonadal males who underwent TRT have revealed higher levels of libido than those who did not. Research conducted on the efficacy of TRT in treating reduced male sexual function has suggested, however, that there is a threshold beyond which TRT does not enhance sexual function further. Of the various types of TRT available, transdermal testosterone substitution has shown particularly positive results in terms of sexual function, mood and fatigue.
Improvement in Bone Mineral Density
Men who suffer from reduced testosterone levels are at a greater risk of osteoporosis, osteopenia and fracture because the hormone plays a crucial role in bone mineral density. Testosterone replacement therapy has resulted in definite improvements in the BMD of hypogonadal men. The results of trials conducted on hypogonadal men receiving TRT have shown increments in spinal, trabecular, and cortical bone density. Besides this, enhancement of the paraspinal muscle region has also been seen which makes TRT a good treatment for maintaining the physical fitness of hypogonadal males. Intramuscular testosterone replacement has been more effective in improving lumbar bone density than transdermal replacement according to trials.
Improvement in Muscle Mass, Strength and Body Composition
As men grow old, their body composition changes considerably with diminished fat free mass and incremented and redistributed fat mass. These changes can increase both morbidity and functional limitations. Replacement of testosterone through therapeutic mechanisms has shown promise as a countering agent to these changes. The administration of testosterone supplements enhances body composition by lowering fat mass and increasing lean muscle mass according to studies conducted on elderly men. These studies did not reveal a significant change in body weight but muscle mass did show a moderate (+2 kg) increase along with grip strength and arm circumference.
Testosterone replacement therapy also showed improvements in muscle strength of upper and lower extremities as well in functional parameters according to studies. The results from these studies do indicate a positive correlation between the aforementioned bodily properties and testosterone supplementation but are not exhaustive enough to provide concrete proof.
Improvement in Energy, Mood and Wellbeing
The effect of testosterone on the mood, wellbeing and energy of hypogonadal men is variable, with conflicting results from various studies. Randomized controlled tests of TRT revealed definitive improvements in their quality of life – including fatigue and wellbeing. TRT also holds promise as an effective antidepressant for men with low testosterone levels, and may even be used to enhance existing anti-depression therapy. The positive effects of TRT on depression patients, in one study, where shown to be persistent. It is to be noted that these improvements were only seen in subjects who had low testosterone levels – which implies that TRT is effective in combating depression only up to a certain threshold of testosterone levels. The underlying factors behind the depression curbing effects of TRT could be the hormone itself or the positive effects it causes.
The Massachusetts Male Aging Study, on the other hand, was unable to find a relation between testosterone levels and depression symptoms. The reason for this could be the fact that there is only a certain genetic classification of individuals who suffer from depression as a result of lowered testosterone levels.
Enhanced Cognitive Function
Declining bioavailable testosterone levels can result in recued verbal and visual memory. A Baltimore Longitudinal Study of Aging or BLSA, that targeted the risk of Alzheimer’s disease showed a reduction of 26% for each 10 unit increment in free testosterone – at two, five and ten years before diagnosis.
There is reliable evidence for a strong link between testosterone levels and brain performance such as mathematical reasoning and spatial abilities. Supplementation of testosterone has improved verbal fluency and spatial cognition in older men suffering from reduced testosterone levels. Furthermore, in those older men who do not suffer from dementia, it has also led to a reduction in working memory errors.
Metabolic Syndrome and Type 2 Diabetes, Cardiovascular Disease
Hypogonadal men often suffer from some form of metabolic syndrome i.e. obesity, glucose regulation impaired dyslipidemia, hypertension and insulin resistance. Reduced testosterone levels and sex hormone-binding globulin can predict the onset of metabolic syndrome in both obese men and those with 25kg BMI according to cross-sectional and longitudinal studies.
That being said, there are insufficient studies to prove that TRT has a concrete beneficial effect for those suffering from metabolic syndrome.
Side Effects of Testosterone Replacement Therapy
The determining factor for developing side effects of testosterone replacement therapy is dependent upon the life circumstances, age and additional medical conditions of the patient. The most frequently discussed risk of TRT is to the prostate gland – prostate cancer and aggravation of benign prostatic hypertrophy are examples of side effects. Moreover, liver tumor and toxicity, worsened sleep apnea, gynecomastia, congestive heart failure, skin diseases and infertility are also sometimes associated with testosterone replacement therapy. Because TRT employs exogenous testosterone that causes suppression of the HPT axis, it isn’t recommended for those who are interested in fathering a child.
Prostrate Related Side Effects of Testosterone Replacement Therapy
TRT is used to normalize the testosterone levels in aging men suffering from late-onset hypogonadism, but has negligible impact on the prostate tissue androgen levels and cell functions, causing no considerable harm to the health of the prostate gland. At present, there is a dearth of conclusive evidence that connects testosterone replacement therapy to an increased risk of benign prostatic hyperplasia or prostate cancer.
Benign prostatic hyperplasia requires androgen presence to develop, and testosterone supplementation increases the volume of the prostate with a gradual, mild increase in prostate specific antigen levels in aged men. In spite of the fact that a meta-analysis revealed that there was a considerable increase in prostate events in men undergoing TRT, the larger part of these events was due to the biopsy of the prostate gland.
Conversely, several studies have been unable to show any noticeable worsening of voiding symptoms associated with benign prostatic hyperplasia among those being treated with testosterone supplements, and there have been no instances of urinary retention, no change in rate of flow urine or residual volumes of urine, and no prostate voiding symptoms either.
Lastly, there is also no significant data that points to a connection between testosterone replacement therapy and lower urinary tract symptoms or acute urinary retention. There is a slight contraindication to this in severe LUTS, as a result of BPH, but it no longer applies after the lower urinary tract obstruction is successfully treated.
Prostate cancer also has reputation of being an ailment that is sensitive to androgens, and it has been treated in ways that bring down testosterone levels. The prevalence of this condition in studies that aimed at finding a connection between it and testosterone replacement therapy was comparable to that among the general population.
As far as now, there has been no compelling proof that testosterone causes prostate cancer. The prevalence of prostate cancer actually increases at the point in a man’s life when testosterone levels begin to decline. At a 19 month median, hypogonadal patients who had prostate cancer in the past did not show any signs of prostate specific antigen recurrence, but did experience the positive effects associated with testosterone therapy. A retrospective study wasn’t able to show a connection between risk of prostate cancer and testosterone either.
However, for those who are already suffering from prostate cancer, testosterone can lead to the stimulation of growth and exacerbation of symptoms. Those who have successfully recovered from the ailment but suffer from hypogonadism can be treated through testosterone replacement therapy, but only after a careful interval during which they are inspected for residual cancer.
All men, wishing to undergo testosterone replacement therapy, who have an existing high risk of prostate cancer or elevated PSA levels should undergo a prostate biopsy to ensure that they do not have cancer of the prostate. To sum it up, there is no compelling evidence of an existing connection between TRT and risk of prostate cancer and it can be used on those who have suffered and then fully recovered from prostate cancer after thorough inspection.
Both malignant and benign liver tumors, hepatotoxicity, intrahepatic cholestasis and liver failure have been previously linked to testosterone replacement therapy. However, these adverse effects do not have an apparent link to intramuscular or transdermal injections. It is for this reason that all oral testosterone supplementation, except testosterone undecanoate, is not recommended. Additional liver abnormalities linked to TRT include carcinoma, hepatocellular adenoma and Peliosis hepatitis.
There is a connection between elevated testosterone levels and elevated hemoglobin levels, in all likelihood due to the stimulatory effect the hormone has on erythropoiesis. Although hemoglobin level reduction caused by hypogonadism can be treated through TRT, it may exceed the normal value after treatment leading to adverse effects, especially in older men.
The increase in the viscosity of the blood can worsen vascular disease, particularly in those people who already have conditions that can cause secondary polycythemia. Testosterone injections have a greater chance of causing polycythemia then topical delivery methods – one study noted that polycythemia occurred in just 5.5% of those users who applied scrotal transdermal testosterone. There isn’t yet an explicit threshold for healthy hemoglobin levels, but dose adjustment to maintain levels below 52% to 55% are recommended.
Other Effects of TRT
Some other side effects linked to testosterone supplementation such as excessive sex drive, aggression, physical/psychological dependence, withdrawal syndromes have occasionally been reported in association with testosterone replacement therapy but there is no validity that testosterone was the underlying cause in these. A study of men with low levels of testosterone and early to mild cognitive impairment, who underwent 12 weeks of TRT, was unable to find any noticeable behavioral or functional changes in the subjects.
Gynaecomastia is a side effect of testosterone supplementation. This benign complication occurs due to aromatization of the hormone into estradiol in peripheral fat / muscle tissue. Even the ratio of testosterone to estradiol remains normal when this occurs. Gynaecomastia is particularly prevalent when testosterone cypionate or enanthate are used and may require adjustment of dosage if the treatment is ongoing.
Reduced size of the testicles and an adverse effect on fertility due to TRT occur due to gonadotropin down-regulation. This has led to ongoing research on the practicality of the usage of exogenous testosterone as a male contraceptive.
The men who are part of this research usually develop azoospermia within roughly 10 weeks of starting therapy and the sperm count rebounds to baseline levels with 6 to 18 months of ceasing therapy. A return to normal fertility rates has been demonstrated after ceasing the therapy. Azoopsermia and diminished testicles may be caused be caused by above normal dosages of testosterone.
Testosterone supplementation has also been linked to worsening of sleep apnea. The hormone does not affect the upper airway dimensions but there is a high probability that it has a role in sleep disorder breathing through central mechanism.
If worsening of sleep apnea symptoms is detected, a formal sleep study of the patient undergoing TRT is warranted and the symptoms are treated through continuous positive airway pressure – if CPAP fails to alleviate the sleep apnea, the TRT dosage must either be reduced or ceased altogether.
A number of skin reactions, primarily pruritus or erythema, have also been associated with transdermal TRT – particularly with testosterone patches rather than gel preparations. Besides this, intramuscular testosterone injections can result in soreness, local pain, bruising, nodules, erythema, swelling or furuncles. Excessive dosage of these androgens may also lead to development of acne.
Future Prospects of TRT
Hypogonadism might present to several specialties. In the past, late-onset hypogonadism was not clearly understood and the studies conducted on the issue up until now were not sufficient to deal with long term negative effects of the condition.
There is a need for large scale clinical trials, or at the very least, a meta-analysis of the extensive existing short term data in conjunction with the long-term expertise that many physicians have now accumulated after working in the field. This will help in the true assessment of the long term risks and benefits of testosterone replacement therapy in aged men who suffer from hypogonadism.