Testosterone deficiency: diagnosis, assessment and treatment

For a diagnosis of testosterone deficiency (TD) — or male hypogonadism — to be made, a male patient should present with evidence of a reduction in serum testosterone levels, as well as sexual, psychological and physical symptoms affecting their physical and mental wellbeing.

A large observational cohort study of more than 1,000 patients in the United States demonstrated a clinically significant increase in prevalence of hypogonadism with increasing age^[1]
. The European Male Ageing Study (EMAS), a large multinational survey of men aged 40–79 years, demonstrated a decline of free testosterone (FT) levels of 1.3% per year in males aged 40–79 years, which increased to 5.1% per year in a subpopulation analysis of males aged 70–79 years^[2]
. The overall prevalence of symptomatic hypogonadism, assessed by biochemical changes and sexual symptoms, was 2.1%. Normal levels of testosterone were measured in 76.7% of the population studied in EMAS, suggesting that ageing alone was not the sole contributing factor to TD^[2]
. In addition to ageing, TD has been associated with an elevated body mass index (BMI ≥25), chronic diseases such as type 2 diabetes mellitus (T2DM) and COPD, as well as hypertension and hyperlipidaemia^[2],[3]
.

This article will discuss the signs and symptoms associated with TD, as well as the available management options.

Pathophysiology and aetiology

Gonadotropin-releasing hormone (GnRH) stimulates the release of two gonadotropins — luteinising hormone (LH) and follicle-stimulating hormone (FSH). This process is initiated at puberty. Testosterone is mainly produced in the testes by Leydig cells; however, around 5% is also produced by the adrenal glands (located on the top of each kidney).

Testosterone exerts its action through binding to and activation of androgen receptors in the target tissues. It has an important role in the male reproductive system (spermatogenesis requires adequate levels of intratesticular testosterone) and it also influences muscle mass, erythropoiesis, bone mineral composition, fat metabolism and cognition^[4]
. Around 60% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) and is not bioavailable, around 38% is bound to albumin and around 2% is unbound (i.e. FT) and is bioavailable. Normal levels of testosterone are regulated and maintained by the hypothalamic–pituitary–gonadal (HPG) axis. A disruption of this pathway can cause TD.

In primary TD, there is a defect in the testes (‘testicular failure’). This condition is associated with low testosterone and elevated LH and FSH (see Table 1).

Secondary TD can occur as a result of pituitary abnormalities. If left untreated, this can result in male infertility, which may be the presenting complaint from patients^[5]
. The effect of testosterone can also be reduced if the problem is at the level of the androgen receptor in cases of androgen resistance or insensitivity.

Typically with increasing age, SHBG also increases, leaving less biochemically active FT. However, in obese men or men with chronic conditions such as diabetes, SHBG can be low in the presence of a normal total testosterone (TT) level, resulting in a normal FT level^[6],[7]
. This difference is important to consider when making decisions to treat TD based on TT alone, as it can result in overtreatment. TD development in older age (usually over the age of 40 years), also known as late-onset hypogonadism or adult-onset hypogonadism, can give a mixed picture in terms of the hormonal profile. As it is more prevalent in men with chronic diseases or obesity, it is difficult to attribute the cause of TD to ageing alone. Older men do not usually have high LH in the presence of low testosterone unless there is a primary testicular cause.

Table 1 provides a summary of the forms of TD and their common causes.

Certain medicines can also cause TD by affecting the HPG axis (see Box 1). These include dopamine antagonists (e.g. risperidone and metoclopramide), glucocorticoids and opioids. In the case of opioids, this is thought to be secondary to its effect at the hypothalamus causing suppression of GnRH^[5]
.

Diagnosis

TD is frequently unrecognised and undiagnosed because signs and symptoms may be non-specific, or may overlap with other common conditions (e.g. depression). The diagnosis of TD is made in the presence of both symptoms and signs of TD and a low serum concentration of testosterone. Total serum testosterone is usually sufficient in making a diagnosis; however, in the case of borderline levels, measuring FT can be helpful.

Symptoms of TD can be classified as sexual, cognitive or physical (see Box 2). Sexual symptoms (low libido, erectile dysfunction and decreased early morning and nocturnal erections) are most often associated with TD^[4],[8]
. Analysis of data on more than 3,200 men found that three sexual symptoms of infrequent morning erections, low libido and erectile dysfunction, together with a decreased ability to perform a vigorous activity, low mood and fatigue, were significantly related to a low testosterone level^[9]
.

History taking and questionnaires

Symptoms of hypogonadism are listed in Box 2 and should be addressed during history taking.

When reviewing the patient’s drug history, the use of recreational drugs (e.g. cannabis), anabolic steroids or testosterone supplements, as well as alcohol intake, should be covered^[4]
. It is also important to assess and exclude systemic illnesses, signs of malnutrition and malabsorption, as well as ongoing acute disease^[5]
.

Screening questionnaires, such as Androgen Deficiency in Aging Males, are available. Although this questionnaire has demonstrated good sensitivity, it has poor specificity and, therefore, is not recommended for the diagnosis of TD by international or European guidelines^[10],[11]
. The Aging Males’ Symptoms scale is a validated questionnaire that can be used, and has been endorsed by the British Society for Sexual Medicine^[4],[12]
.

Physical examination

Testicular examination is normally required to determine size and consistency. Clinicians should also note the distribution and presence/absence of body hair (including beard growth and pubic hair) and general physical status to gauge muscle mass^[5]
. In patients aged over 55 years, digital rectal examination should be considered to assess prostate size and consistency, and look for signs of prostate cancer (e.g. a nodular or irregularly hard prostate). The patient should be counselled and offered a prostate specific antigen (PSA) test. Further investigations for prostate cancer should be carried out if any abnormalities are identified. This is especially important when considering treating TD with testosterone replacement therapy (TRT), where a new diagnosis or active prostate cancer is a contraindication to treatment.

The patient’s waist circumference and BMI should be measured, as an elevation of either is a risk factor for TD^[5],[13]
.

In older men, there may be an overlap of these symptoms with other differential diagnoses, such as depression, diabetes mellitus, peripheral vascular disease, or the normal ageing process, which should also be considered.

Investigations

Owing to the diurnal variation of testosterone, serum testosterone should be assessed on two occasions between 7:00 and 11:00^[4],[14]
. Guidelines suggest that serum testosterone should also be assessed in the fasting state to avoid the reduction in testosterone that occurs following glucose ingestion^[5],[15]
. The British Society for Sexual Medicine’s guidelines also support taking the first serum testosterone measurement in the fasting state and suggest that this can be done alongside other relevant tests that should be performed at this time, such as fasting glucose and cholesterol^[4]
.

The normal range for total serum testosterone (free and bound) is 8–12 nanomol/L. Studies have demonstrated an increase in the prevalence of TD symptoms as serum testosterone levels decrease^[9]
. The EMAS assessed the probability of symptoms occurring in TD and gives the TT threshold of 8.5 nanomol/L for erectile dysfunction and 11 nanomol/L for reduced morning erections^[5]
. No threshold was identified for physical or psychological symptoms^[9]
.

When results are borderline and close to 12 nanomol/L, FT should also be checked. This is an assessment of the bioavailable testosterone and can be measured provided SHBG and albumin levels are available^[16]
. This can be done using an online FT calculator, such as the one provided by the International Study of the Ageing Male. SHBG can also be assessed when TT is borderline or close to 12 nanomol/L, especially in patients who are obese or of an older age. Measurement of FT should be considered prior to making a decision to commence TRT based on a low TT level alone
^[7]
.

For all patients with low testosterone levels (<12 nanomol/L), LH levels should be assessed to help differentiate between primary or secondary TD. In the case of very low TT (<5.2 nanomol/L) associated with low gonadotropins, or when pituitary pathology is suspected, prolactin levels should be checked to rule out conditions that may cause hyperprolactinaemia^[4]
. If an elevated prolactin level is confirmed, an MRI scan of the pituitary gland should be performed to exclude a pituitary adenoma^[4],[17]
. In such cases of very low testosterone, relevant investigations should be performed to identify a possible underlying cause, such as those listed in Table 1.

It is well recognised that erectile dysfunction and hypogonadism can be a sign of cardiovascular disease and, as part of the initial assessment, a patient should be assessed for cardiovascular risk factors and have a fasting glucose and lipid profile completed.

Treatment

The aim of testosterone treatment is to restore physiological androgen dependent functions and to improve the patient’s quality of life (e.g. sexual function, muscle strength and bone mineral density). In men with late-onset hypogonadism, while the focus of treatment should be to relieve the impact of chronic conditions and optimise lifestyle modifications prior to TRT, this may not always be possible.

Testosterone therapy

Patients who have both a low serum testosterone level and show symptoms of TD should be offered treatment. For symptomatic patients, making the correct diagnosis and initiating treatment to reach normal levels of serum testosterone can significantly improve quality of life.

In the presence of symptoms, a TT level of <8 nanomol/L or a FT level of <180 picomol/L requires treatment. A TT level of >12 nanomol/L or a FT level of >225 picomol/L is considered within normal limits and does not require any treatment with TRT^[8]
. Table 2 summarises the treatment guidelines recommended by British and international sexual medicine societies.

In patients with compensated TD (i.e. with an increased LH and TT of <12 nanomol/L), treatment should be considered. Similarly, in symptomatic patients with an increased LH and normal TT levels, TRT should be offered; the long-term clinical consequences of an elevated LH are unclear^[4]
.

Concerns and contraindications

Prior to starting TRT, patients should be assessed to rule out the contraindications listed in Box 3. As part of the investigations in patients considered for TRT, a baseline haematocrit and haemoglobin test should be performed. Testosterone promotes erythropoiesis through its action on the kidneys and can, therefore, induce hyperviscosity and increase risk of thrombosis. Consequently, a haematocrit of >0.54 is a contraindication to TRT^[5]
.

Concerns have been raised with TRT and its effect on cardiovascular disease and all-cause mortality. A large study of more than 4,000 patients in the United States found that in those treated to achieve normal levels of testosterone, major adverse cardiovascular events were reduced compared to those with persistently low testosterone over a three-year period of follow-up^[18]
. According to the European Association of Urologists, there is insufficient evidence (Level 1a) to support the concern that testosterone, when returned to physiological levels with TRT, can cause major cardiovascular events^[5]
. Severe chronic heart failure (class IV of the New York Heart Association Functional Classificiation) is a contraindication to treatment^[4]
.

TRT is contraindicated in men who have a history of breast cancer; however, there is no significant evidence that TRT can cause male breast cancer^[5]
.

In patients with active or advanced prostate cancer, TRT is contraindicated. There is no evidence to suggest that a rise in serum testosterone with treatment can cause prostate cancer. This can be explained using the saturation model first proposed by Kaplan et al., which suggests that there is a set level to which androgens can stimulate prostate cancer growth^[19]
. This finding is also supported by a randomised control trial in 40 men with TD who underwent a prostate biopsy pre- and post-TRT at six months to assess change in prostate tissue androgen levels. This study found no significant increase in testosterone levels of prostate tissue despite an increase in serum testosterone levels^[20]
. In patients with a history of prostate cancer, TRT can be offered after one year of follow-up and in the absence of any PSA recurrence. These patients should be carefully assessed for risk and TRT should be offered to those with a low risk of prostate cancer recurrence^[5]
.

Patients who wish to preserve fertility

TD is associated with male infertility and can be diagnosed during investigations performed for infertility. In such patients, or in those who have a desire to have children, TRT should not be offered as first-line treatment. TRT through the negative feedback pathway suppresses pituitary LH and FSH and, consequently, intratesticular testosterone and spermatogenesis^[5]
. In fertile patients, treatment of hypogonadism may be desired to treat symptoms and to optimise spermatogenesis by elevating intratesticular testosterone. In such cases, human chorionic gonadotropin (hCG) hormone or oestrogen modulators can be offered to patients in an attempt to elevate intratesticular testosterone levels and maintain spermatogenesis. In patients with hypogonadotropic hypogonadism, hCG can be administered subcutaneously to increase circulating gonadotropins, which can subsequently elevate testosterone and spermatogenesis.

Selective oestrogen receptor modulators (e.g. clomiphene citrate) act as oestrogen receptor antagonists at the level of the hypothalamus, thereby increasing gonadotropin release through inhibition of oestrogen feedback^[21]
. Consequently, therapeutic testosterone levels can be achieved in patients, while preserving spermatogenesis. Aromatase inhibitors, such as anastrozole, are another class of oestrogen modulators that act to reduce peripheral aromatisation of testosterone to oestradiol, thereby reducing the negative feedback of oestrogen on the hypothalamus. It can also be considered as an off-licence alternative for men with hypogonadism who wish to preserve fertility^[22]
.

Patients with diabetes

A double-blind placebo-controlled study in patients with T2DM clearly demonstrated a significant improvement in sexual function and patient-reported quality of life^[23]
. Other benefits demonstrated include an increase in bone mineral density and haemoglobin levels^[24],[25]
.

Route of administration

The choice of route of administration is guided by patient preference, ease of use and cost. Usually, a short-acting preparation is started to allow observation in case of adverse effects. Once stabilised on TRT with no significant adverse effects, a long-acting agent may be offered^[5]
.

TRT is available as an oral preparation, intramuscular injection, subdermal depots and transdermal gel, intranasal gel or patches (see Table 3). However, patients should be advised that the transdermal gel can be transferred during interpersonal contact.

Lifestyle modifications

TD is often associated with obesity and chronic diseases such as T2DM. Lifestyle modification and weight-loss advice, together with the optimisation of therapy for chronic diseases, should be an important first step in the treatment of such patients^[4],[5]
. This is supported by a recent systematic review that demonstrates an increase in testosterone, SHBG and gonadotropins after bariatric surgery^[26]
.

Patients should be informed that a significant improvement is often seen in people commencing TRT in combination with lifestyle modifications^[27]
.

Follow-up

Patients started on TRT should be followed-up regularly to monitor for adverse effects. Current guidelines recommend follow-up at 3, 6 and 12 months, and annually thereafter. At each visit, the serum testosterone, haematocrit and PSA should be assessed. There is no set optimum level of TT to be achieved; therefore, the aim is to reach TT levels in the mid-normal range^[4],[5]
. Serum testosterone should be checked 8–12 hours after application of the transdermal gel, as peak concentration that exceeds the average concentration has been found at 2–4 hours^[28]
. No set time is required for those on intramuscular injections.

Men with pre-existing cardiovascular disease should be monitored carefully. TRT can cause fluid retention in those with heart failure. If the haematocrit rises to >0.54, TRT should be stopped and re-introduced at a lower dose, or in joint care with the haematologist for consideration of the necessity of periodic venesection^[5]
.

If a significant and continuous rise in PSA is seen, notably above the age-specific range, a digital rectal examination should be carried out and the patient should be referred to a urologist for further investigations for prostate cancer^[5]
.

Conclusion

TD often occurs in obese patients with chronic diseases (e.g. T2DM and metabolic syndrome) and, in these cases, the co-existing condition should be treated and optimised first. Lifestyle modifications and weight loss should be advised to optimise general health and wellbeing, and improve testosterone levels. Failing this, if TRT is to be started, patients should be counselled about the potential risks and controversies surrounding the therapy.

TD can affect male psychological, sexual and physical health. Making a correct diagnosis can alleviate this and lead to an improvement in quality of life.