It is vital to understand that even the best TRT protocol is not as effective as a healthy Hypo-Pituitary Gonadal (HPG) axis. In a healthy individual, there is diurnal variation of your hormonal levels, something that can’t be replicated, even with a stable TRT protocol. Have a read of The Perfect TRT Protocol. This fluctuation occurs for a reason. There are periods when your body is supposed to be predominantly catabolic, and periods when your body is supposed to be predominantly anabolic.

If you don’t need TRT, you shouldn’t be prescribed hormone replacement therapy. There are no guarantees that your axis will restart if you ever decide to stop. TRT should be entered into ‘eyes-wide-open’. Saying that, if you actually need TRT, no one ever regrets going on therapy.

Your doctor should take a thorough history, perform a physical examination and conduct the appropriate blood investigations, +- MRI brain / USS testes before starting you on your road to recovery.

It is Important To

Establish a Diagnosis

Primary Hypogonadism

Low testosterone resulting from a problem within the testes. In primary hypogonadism the Lutenising Hormone (LH) and Follicle Stimulating Hormone (FSH) is elevated as it’s trying to stimulate the testes into producing testosterone.

Secondary Hypogonadism

Low testosterone resulting from a problem within the hypothalamus and/or pituitary. In secondary hypogonadism, the brain isn’t able to respond to the low testosterone and so LH and FSH are low.

Mixed Hypogonadism

Self explanatory.

Establish a Likely Cause

Whilst you may have a high level of suspicion for the cause of your male hormone deficiency, there is little or no way to prove causation without pre and post event blood work. Symptoms are subjective.

Identify Differential Diagnosis

These may be contributing towards your symptoms, they may even be the cause of your symptoms. Not everything is related to testosterone. Addressing these may prevent you from needing TRT, they may also enable you to feel the benefits of TRT. It’s important to have a holistic approach to patient care.

Identify, Address and Correct

Lifestyle Issues

Nutrition

Physical Exercise.

If you have true Testosterone Deficiency Syndrome (TDS), it’s unlikely that you will restore your testosterone to an optimal level, however, it’s important to address these factors for overall health, not just improve your testosterone level. Have a read of my 10 Testosterone Commandments.

Factors to Take into Consideration Prior to Deciding on Best Treatment Option

Age

Snowies should consider the short acting gel in case of side effects, or if you are unsure of committing yourself to lifelong injections when the gel can be effective. Consider potential dose reduction due to decreased utilisation and/or activity levels.

Body Habitus

An increase in visceral and peripheral fat distribution raises the likelihood of aromatisation of testosterone to oestrogen. Consider more frequent dosing, a lower dose, subcutaneous over intramuscular administration. Consider the use of an aromatase inhibitor under strict supervision by your prescribing clinician.

Liver Health

Liver dysfunction raises SHBG which reduces your bioavailable androgen level. This may lead to you needing a higher than typical dose to attain optimal levels. It also increases the risk of aromatisation of testosterone to oestrogen.

Sex-Hormone Binding Globulin (SHBG)

SHBG binds to testosterone to prevent it from being bioavailable. Therefore, it is important to identify and correct a high SHBG if appropriate. Patients should be counselled that the qualitative effects of TRT may take a little longer than their counterparts. It is worth noting that TRT often decreases SHBG so caution should be applied to the convenience of long injection intervals and infrequent review.

Alcohol Consumption

Alcohol is a toxin, it increases aromatisation of testosterone to oestradiol in the liver.

Type of Hypogonadism

If you have a primary hypogonadism, HCG is unlikely to stimulate a significant rise in intratesticular testosterone production, compared to men with a secondary hypogonadism. This is worth noting when deciding on your HCG dose and frequency.

Compliance

It is important to consider which TRT will best suit your needs, goals and lifestyle. It may be necessary to have a benefit/risk discussion with your doctor to decide on which protocol would be most appropriate. This should be a joint decision as the doctor is working with your best interests at heart. Ok, not all… most. I definitely am!

Cost

There is a cost implication with each TRT option that must be taken into account before therapy is started.

Treatment Options

Testosterone Enanthate/Cypionate + Human Chorionic Gonadotropin

Testosterone Enanthate/Cypionate

Testosterone Gel + HCG

Testosterone Gel

Mesterolone – Suitable for guys with a normal total testosterone but elevated SHBG

Administration Route

Intramuscular

Injection into the muscle, fast and effective absorption due to the high vascularity of muscle.

Subcutaneous

Injection into the area between the skin and the muscle, slower absorption potentially reducing spikes in hormonal levels as the tissue is less vascular.

Topical

Gel or cream applied directly onto the skin, less invasive but potential inconsistent absorption.

DIAGNOSIS

Causes of Primary Hypogonadism

Klinefelter Syndrome

A condition in males who have XXY sex chromosomes, rather than the usual XY.

Bilateral Anorchia

A rare condition in which one or both testes are absent in a phenotypically and genotypically normal male.

Cryptorchidism

A condition in which one or both of the testes fail to descend from the abdomen into the scrotum.

Bilateral Orchiectomy

A surgical procedure where both testes are removed.

Other Organic Aetiology

Trauma / infection to the testes.

Causes of Secondary Hypogonadism

Panhypopituitarism

A condition of inadequate or absent production of the anterior pituitary hormones.

Congenital Hypogonadotropic Hypogonadism

A rare disorder of sexual maturation characterised by gonadotropin deficiency with low sex steroid levels associated with low levels of follicle stimulating hormone and luteinising hormone.

Constitutional Delay of Puberty

A term describing a temporary delay in the skeletal growth and thus height of a child, with no physical abnormalities causing the delay.

Hypothalamic or Pituitary Tumour, Destruction or Infiltrative Disease

Such as a pituitary adenoma, traumatic brain injury, pituitary or intracranial surgery, radiation therapy, infection, haematochromatosis.

Androgenic Anabolic Steroid (AAS) Use

Through suppression of the hypo-pituitary gonadal (HPG) axis from exogenous synthetic testosterone use.

Hypothyroidism

Causes inhibition of hypothalamic and pituitary production of lutenising hormone.

Toxins

Medications, illicit drugs, alcohol.

HISTORY

Typical Symptoms of Low Testosterone:

Lack of energy

Loss of drive and determination

‘Brain Fog’

Depression

Anxiety

Depersonalisation

Loss of libido

Typical Signs of Low Testosterone

Erectile dysfunction

Loss of lean muscle mass

Increase in visceral fat

Decreased bone mineral density

PHYSICAL EXAMINATION

This includes a basic physical examination including blood pressure, genital examination and the dreaded prostate examination if you are over 40 years old.

INVESTIGATIONS

‘TRT Complete’ Blood Test

The test can be ordered from the Order Your Blood Test page of our website, and includes the following tests:

Total Testosterone

The male sex-hormone. This level must be taken in context alongside the patient’s symptoms, age and other biological factors. It is NOT a particularly useful marker of actual bioavailable hormonal health. Free testosterone, oestradiol and dihydrotestosterone are the bioavailable hormones.

Free Androgen Index / Free Testosterone

This is the bioavailable, ie. usable, androgen / testosterone level. It is often associated with the positive effects of testosterone such as libido, drive and determination. However, high free testosterone can actually cause a drop in libido and anxiety. Have a read of TRT – Chasing Numbers.

Prolactin

An important hormone involved in immunity and sexual function. Grossly elevated levels (>500) alongside low LH and FSH raise the suspicion of a potential pituitary adenoma which requires further investigation (MRI brain).

Oestradiol

Testosterone is metabolised in part to oestrogen, which is necessary for a healthy libido, cardiovascular and bone health. Oestrogen is the main feedback hormone to the hypothalamus and pituitary, helping to regulate the HPG axis.

Follicle Stimulating Hormone

FSH is understood to stimulate the Sertoli cells of the testes to help maturation of sperm.

Lutenising Hormone

LH stimulates the Leydig cells of the testes to produce testosterone. There is evidence it up-regulates some of the other steroid-hormones in the cascade down from Pregnenolone. It is also believed to bring about a qualitative improvement in symptoms of well-being as there are LH receptors in the brain.

Full Blood Count

A raised haematocrit can cause symptoms such as lethargy and dizziness. In conjunction with an elevated blood pressure, this can increase your chances of potentially having a heart attack or stroke.

Prostate Specific Antigen

TRT does not in itself cause prostate cancer. It makes perfect sense that healthy ratios achieved through TRT would actually be protective. That being said, prostate cancer is androgen-receptive, so it can make the cancer more aggressive. Your PSA should be monitored as a matter of routine.

Urea & Electrolytes

The kidneys excrete toxins, urea and excess water from the body. Kidney dysfunction is associated with elevated blood pressure which is of particular importance when considering the potential implications or raised haematocrit. Reduced elimination of the metabolites of testosterone means that a lower dose may be necessary to achieve optimal levels.

Liver Function Tests

The liver helps to metabolise chemicals and remove toxins from the body. Liver dysfunction can result in increased aromatisation of testosterone to oestradiol.

Sex Hormone Binding Globulin

SHBG is the most important hormone in deciding what protocol you should be on. Whilst there is some controversy regarding the exact role of SHBG, we know it binds to testosterone to prevent it from being used. Testosterone predominantly exerts its anabolic effects when you are resting, your SHBG is lower at night so it stands to reason that it prevents excess testosterone release when you are in a catabolic state. When it comes to designing and amending your TRT protocol, it’s the first thing I look at. If it’s not being monitored, you are not being effectively monitored.

Ferritin

HbA1C

Healthy testosterone levels can improve insulin sensitivity thereby decreasing your risk of Type 2 Diabetes Mellitus.

Lipids incl. Cholesterol

Supraphysiological free testosterone levels can have a negative impact on HDL-cholesterol. Cholesterol is the precursor to Pregnenolone, the ‘father’ hormone to your steroid hormones.

Thyroid Function Tests

Hypothyroidism can mimic a number of the symptoms associated with low testosterone. It can also suppress LH production within the hypothalamus and pituitary, resulting in a secondary hypogonadism. Hyperthyroidism can be a cause of elevated SHBG, resulting in decreased androgen level bioavailability.

MRI Brain

The primary goal of this is to exclude a pituitary adenoma. It is indicated by a raised prolactin (>500), with an associated secondary hypogonadal blood picture (low LH and FSH). Any symptoms such as headaches and visual disturbance should be noted.

Ultrasound Testes

To exclude any pathology in the scrotum.

­­­­­­­­­

TREATMENT OPTIONS

Testosterone Enanthate/Cypionate + HCG

The GOLD standard when it comes to TRT. To understand why this is the case, you need to have an understanding of the HPG axis and what we are trying to achieve… stability. I’d say balance but that word is banned!

Put very simply:-

Testosterone Enanthate to replace the testosterone

HCG to replace the LH

Testosterone Enanthate is a single short-acting ester which makes dosing and managing side effects predictable. Complications, such as high oestrogen, can normally be managed by dose alteration and adjustment in the frequency of administration. Very rarely is an aromatase inhibitor used, less than 5% of my patients are on one.

HCG mimics LH. It is disappointing that HCG levels cannot be measured using the LH diagnostic blood test. Most guys note a fullness in their testes with use of HCG alongside testosterone. A major reason for using HCG is to help preserve fertility. I can confirm this has been successful for at least two of my patients!

Testosterone Enanthate/Cypionate Monotherapy

Taking all the above factors into consideration, it isn’t unreasonable for a patient to decide that he doesn’t want to use HCG in his protocol. A perfect protocol would have HCG in it, have a read of The Benefits of Using HCG with TRT. Sometimes it isn’t feasible, whether it be due to lifestyle constraints or co-morbidities that may make stability unachievable. It should be noted that patients on TE monotherapy can complain of testicular shrinkage.

Testosterone Gel + HCG

I have patients who are perfectly happy using the gel and HCG and have no intention of changing to the injections. Their numbers are great and they feel fantastic, why would they want to switch? If the aim of TRT is health and a feeling of well-being, your treatment choice is down to you and its effect on you.

Testosterone Gel

This is a perfectly reasonable choice of TRT. It’s a daily application gel that can provide stable physiological levels within days. Some guys do struggle to achieve adequate levels, most likely due to inadequate and/or inconsistent absorption rates. Titration of dose according to effect is also a rather blunt process. There is concern over the potential for direct skin to skin transfer. It is therefore best applied to an area that isn’t in direct contact with anybody else for up to 6 hours. Swimming or showering soon after application can reduce its effectiveness.

Mesterolone

A Dihydrotestosterone (DHT) derivative that can be used to increase DHT levels and the bioavailability of androgen levels due to it binding to SHBG. It can also work as a partial oestrogen antagonist. Can be effective in men with normal testosterone levels who have high SHBGs.

SIDE EFFECT MANAGEMENT

As discussed, most side effects can be managed with dose adjustment and/or alteration in the frequency and/or route of administration.

Oestrogen

Always a hot topic. Management of symptoms are discussed in the blog TRT – How to Control Oestrogen. There is a place for use of ancillary drugs such as Exemestane, however it’s normally the lazy physician’s approach to TRT.

Raised Haematocrit (HCT)

TRT stimulates erythropoiesis through an increase in free testosterone. This can elevate haematocrit which may cause symptoms such as tiredness and dizziness. It is important to monitor blood pressure if your HCT is elevated as this can potentially increase your risk of cardiovascular complications such as a heart attack or stroke. Most guys note a symptomatic improvement if they keep their HCT <50. It is always sensible to stay hydrated to increase the potential blood volume. If HCT rises, it can normally be controlled by regular blood donations or therapeutic phlebotomy. Very rarely do you need to take prophylactic aspirin, I’m sure significant elevations are a sign of aggressive protocols.

Anxiety

Normally indicative of fluctuating hormonal levels due to being on the incorrect protocol. I see it a lot in my guys who run too high, we reduce their dose and they come back saying that not only are they calmer, their libidos have improved. Repeat after me – MORE IS NOT BETTER!

Acne

This is typically from DHT causing increased sebum production in your sebaceous glands, resulting in spots. It’s not normally troublesome and can be managed by topical acne medication. It can be a sign of an aggressive protocol as you always have a relative decrease in DHT compared to your other hormones, as the concentration of 5 alpha-reductase is highest in the testes.

Male Pattern Baldness

What can I say? Embrace the bald! If you don’t want to do that, try topical Minoxidil and Ketoconazole shampoo. Stay away from poisons such as Finasteride. Google ‘Post-Finasteride Syndrome’, that should put you off.

Obstructive Sleep Apnoea

The link between TRT and OSA is weak, but any changes in sleep quality should be noted and addressed with your doctor. Bad sleep is a killer. We are asleep for a 1/3 of our lives, if the quality of that time is poor – the time we are supposed to be resting, repairing and growing – how are we supposed to function? Continuous Positive Airway Pressure (CPAP) is the treatment, the mask sure ain’t sexy, but it may save your life.

Gynaecomastia

The development of breast tissue can occur despite normal oestrogen and prolactin levels. The use of Tamoxifen should be considered in these guys, with dose titrated according to effect. Unfortunately, some men have to resort to surgery to resolve the issue.

It is important to understand that whilst there are well-recognised TRT protocols freely available on the internet, it isn’t always as easy as that. There can be a big difference between a weekly dose of 125mg and 100mg. There can be a big difference in a stat weekly dose of 100mg, and that same dose split into multiple doses. In addition to the constants you put into your body, your physiology can change on TRT, which means your protocol will need to change with it. Don’t get me wrong, I don’t hear from the vast majority of my guys until it’s their six-month review, they’re so quiet I sometimes think there must be something wrong, only to be reassured at their review that everything is perfect! There is a small cohort of patients that I’m still tinkering with on a regular basis. Without exception they’ve all noted an improvement, but they’re still not quite there yet. We’re not as clever as we think we are, we need to remember to keep it simple and keep it safe.

Dr Robert Stevens MBChB MRCGP Dip.FIPT