The aim of testosterone replacement therapy (TRT) is restoration of your androgen levels to within normal physiological parameters. The aim of testosterone optimisation therapy (TOT) is to optimise your androgen levels so that you feel the qualitative and quantitative benefits of having healthy hormonal levels. They are not mutually exclusive, they should be the same thing.
How is this achieved?
The primary role of hormones is to help maintain homeostasis, a complex process that involves biochemical and physiological mechanisms to help achieve an equilibrium or stability within the body. By that rationale, the aim of TRT and TOT is to achieve stability. The qualitative effects of TRT are due to stable levels with the correct androgen ratio of the different hormones.
How is stability achieved?
For us to understand this, we need to understand both pharmacokinetics, which is what the body does to the testosterone once administered, and pharmacodynamics, which is what the testosterone does in the body.
Route of administration?
It comes as no secret that both intramuscular and subcutaneous injections are the most effective method of delivering a consistent dose of testosterone to the bloodstream. Whilst topical application of testosterone cream or gel remains a reasonable choice of delivery method, there are potential limitations to its efficacy due to inconsistent absorption with the skin barrier.
Pharmacokinetics 1-0-1 & How it Relates to Your Choice of Testosterone Ester
There is considerable variation in the half-life of unbound testosterone, ranging from 10 to 100 minutes. Esters are attached to the testosterone molecule by a process called hydrolysis. Esters are essentially a class of organic compounds that react with water to produce alcohols and organic or inorganic acids. This equates to a chain of carbon atoms that makes the molecule less soluble. The testosterone molecule can only become bioavailable when enzymes from the liver break down the carbon chains releasing the testosterone. The longer the carbon chain, the longer this process takes.
Testosterone Enanthate contains the carboxylic acid ester, enanthoic acid. It has a half-life of approximately 7-9 days. According the British National Formulary, a single dose of 250mg Testosterone Enanthate should be injected every 2-3 weeks(1). According to the manufacturer, a single injection of 250mg leads to an increase in total plasma testosterone between 44.5-60.4 nmol/l (Cmax), which is reached within 0.5 – 5 days post injection. It was also noted that testosterone levels returned to baseline typically after 2 weeks, so the suggested 3-week injection frequency would be ineffective in rising baseline figures(2).
Steady-state mean serum levels of testosterone, bioavailable testosterone (T), dihydrotestosterone (DHT), and estradiol in thirty-three hypogonadal 22- to 65-year-old men given 200 mg of intramuscular testosterone enanthate every 2 weeks. Error bars indicate standard deviations. Dashed lines denote upper and lower limits of normal range. Adapted, with permission, from Dobs et al.7(3).
Sustanon contains a blend of four esters:-
- 30mg Propionate – Half-life approximately 3.5 days
- 60mg Phenylpropionate – Half-life approximately 4.5 days
- 60mg Isocaproate – Half-life approximately 9 days
- 100mg Decanoate – Half-life approximately 15 days
The pharmacokinetic properties of Sustanon are not too dissimilar to that of Testosterone Enanthate. Sustanon has a Cmax of approximately 70nmol/l, which is reached approximately 24-48 h (tmax) after administration. Levels then return to baseline after approximately 21 days, longer than Enanthate, presumably due to the longer half-life of the decanoate ester(4). In theory, this blend of esters with varying half-life’s was designed to reduce the peaks and troughs associated with the metabolism of the testosterone. Unfortunately, in practice, this is not the case.
NEBIDO (Testosterone Undeconate)
Nebido contains the long undecanoic acid ester. Its half-life is approximately 90 days, with stability being achieved in approximately 450 days.
Due to the long-acting nature of this compound, a loading dose is recommended at six weeks. The Cmax 7 days after the first injection was noted to be 38 nmol/L, this rose to 50nmol/l after the 6-week loading dose was administered. Once stable, the mean Cmax was noted to be 37nmol/l and the Cmin was 16 nmol/L, with a 10-week dosing interval. The median intra- and inter-individual variability (coefficient of variation, %) of Cmin values was 22 % (range: 9-28%) and 34% (range: 25-48%), respectively(5).
It is recognised that there is variance of the peak and trough levels between individuals(6), so the data cannot apply to everybody.
The primary aim of TRT is to achieve stable hormone levels within the body so that homeostasis is maintained. The above data demonstrates that the current recommendations regarding dose and injection frequency do not achieve this.
When choosing a testosterone, it’s important to understand how long it will typically take to achieve a ‘steady state’. This is when the rate of drug input is equal to the rate of drug output. Irrespective of your choice, it is impossible to achieve true stability, something I talk about in The Perfect TRT Protocol. It is recognised that it takes approximately 5 half-lives for this to occur.
Steady state according to the different esters available:-
- Testosterone Enanthate – 35 – 45 days
- Propionate ester – 17.5 days
- Phenylpropionate ester – 22.5 days
- Isocaproate ester – 45 days
- Decanoate ester – 75 days
- Nebido (Testosterone Undeconate) – 450 days
The aim of dosing is to build up the plasma concentration of testosterone so that it achieves an optimal level according to your genetics, physiology and utilisation. You cannot predetermine that number based on the current data. The current UK reference range of 12-29 nmol/l is very non-specific, doctors do not take age into consideration despite knowing there is an age-related decline in testosterone. This is an arbitrary discussion since we know there are health benefits in having a testosterone above 19nmol/l(7).
You must first understand that the total testosterone level is not a true marker by which qualitative and quantitive symptoms can be gauged. Total testosterone is not bioavailable, it is simply the precursor to the bioavailable androgens, free testosterone, oestradiol and dihydrotestosterone. It is still important because it must be taken in context with other proteins in the body, such as Sex Hormone Binding Globulin (SHBG) which binds to testosterone preventing it from becoming bioavailable. SHBG serves an important role in helping mediate the transfer of testosterone into the cells for its primary function, cell growth and repair. There is a correlation between low testosterone and low SHBG which has implications for cardiovascular disease and increased insulin resistance(8). Another protein to be taken into consideration is albumin, formed in the liver, which has a weaker affinity for testosterone so still reduces the free testosterone level.
Testosterone is lipid soluble which means it can permeate cell membranes to enter the cell to exert its effects. It has a high volume of distribution, this information helps you calculate the dose needed to achieve a critical plasma concentration. As already mentioned, there is individual variation in drug metabolism of the different esters and there is no defined optimal testosterone level, so you cannot apply a standard fixed dose and frequency of injection to achieve stability. Therefore, to titrate your optimal dose and frequency, it is sensible to use only one variable. It also makes sense that the action of this variable should be predictable, something that has been demonstrated with testosterone enanthate; oestradiol and DHT levels exhibit saturable increases with increased dose(9).
More frequent smaller doses are often better at achieving actual steady levels. SHBG which binds to testosterone is often the determining factor in deciding injection frequency. If the injection frequency is too long, you can reach a steady state, yet that term will be a relative one and you will still notice peaks and troughs as the testosterone is metabolised and excreted by the kidneys as conjugates of glucuronic and sulfuric acids in urine at a high rate.
Gold standard TRT includes Human Chorionic Gonadotropin alongside testosterone. I haven’t gone into The Benefits of using HCG with TRT, or the TRT Management Guidelines, as these have been covered before in previous blogs.
When we opened The Men’s Health Clinic in January 2016, we looked at the various treatment options available in the UK. Nebido (Testosterone Undeconate) was the UK licenced drug for the treatment of Testosterone Deficiency Syndrome. We were enthused by the product description which assured us of realistic steady levels, the absence of peaks and troughs, the need for infrequent injections and there being no direct transfer since it is administered via the intramuscular route. So a direct comparison to Sustanon and Testogel, hence the marketing.
As an aside, Sustanon is an interesting blend of esters, it was designed to achieve stable levels. I have heard a few amusing metaphors justifying the mix of esters. The Propionate ester is the ‘sprinter’, the Phenylpropoionate and Isocaproate esters are ‘middle distance runners’, and the Decanoate ester is a ‘long distance runner’, with each respective ester taking over the baton to keep a constant pace. I mean honestly! Perhaps it made sense after a few glasses of scotch! In practice, it appears that the shortest acting ester, Propionate, is the most important determinant in deciding the optimal protocol for relative stability. So with a normal SHBG, I would recommend every other day injections. However, the high Benzoyl Alcohol content of Sustanon which can cause post injection pain (PIP) makes that a rather unappealing proposition. Sustanon is prescribed because it’s cheap, dirt cheap, sometimes you just get what you pay for. It is difficult to achieve stable levels on Sustanon and providers often resort to an aromatase inhibitor or ‘third leg of TRT’ to reduce oestrogen. I don’t use Sustanon, only the best for my patients!
We opted for Nebido and followed the treatment guidelines, administering a loading dose at six weeks with subsequent follow up bloods twelve weeks later. The vast majority of men had numbers not too dissimilar to pre-treatment levels, along with pituitary suppression of Lutenising Hormone (LH) and Follicle Stimulating Hormone (FSH), something that is expected on TRT. There were a few outliers who had residual pituitary function, these patients were noted to have a primary hypogonadism, their total testosterone levels were still only just above baseline.
Patients using Nebido did report an initial qualitative improvement in their symptoms, however as the weeks went on they noticed a dip or trough, with a return of their symptoms of low testosterone. This essentially negated the argument for a loading dose with the next injection interval being twelve weeks. In response, we decreased the interval between the loading dose and the 3rd dose to ten weeks for new patients. Despite this, patients were still complaining of peaks and troughs. Injection intervals were shortened further over time for our regular patients until reasonable trough levels were achieved. Unfortunately, this raised a further set of problems. As already discussed, the aim of TRT and TOT is to achieve sustainable stable levels that bring about, not only the correct total testosterone level, but also optimal levels of the bioavailable markers; free testosterone, oestradiol and dihydrotestosterone. Shortening the interval between injections brought about sustained symptoms of supraphysiological markers of excess free testosterone, oestradiol and dihydrotestosterone. The temporary issue of a few weeks of some breast tissue swelling, nipple tenderness, water retention and acne was bad enough, but to have sustained symptoms was intolerable.
In view of our experiences with Nebido, we looked to the American model for managing TDS. They were using short-acting esters, such as Cypionate and Enanthate, and were achieving stable levels that were backed up with a noted improvement in their symptoms. Their model was far more progressive, they were not only managing total testosterone, they were also monitoring and managing high oestradiol and dihydrotestosterone. They also considered the benefits of using HCG alongside TRT.
We have had great success in achieving not only sustainable stable levels with the use of Testosterone Enanthate, but also the subjective and objective qualitative and quantitative changes that each patient has sought from TRT. Have a read of the testimonials page of our website to see the positive impact that gold standard TRT, clinical input and care has had on our patients.
Achieving stable levels is all about tailoring injection dose and frequency according to need, and titrating that level up or down according to both qualitative and quantitve markers. I hope it’s now clear why I use Testosterone Enanthate as my GOLD STANDARD TRT here at The Men’s Health Clinic. You cannot have a cookie-cutter approach to TRT. Keep it simple, keep it safe.
Dr Robert Stevens MBChB MRCGP Dip.FIPT