Approach
In primary hypogonadism (PH), the defect lies at the level of the testes ('testicular failure'). PH is associated with low testosterone and elevated gonadotrophins. In secondary (also known as central or hypogonadotrophic) hypogonadism, the defect lies at the level of the hypothalamic-pituitary axis, associated with low testosterone and low (or inappropriately normal) gonadotrophins, and could be isolated hypogonadotrophic hypogonadism (IHH) or combined pituitary hormone deficiency (CPHD).
The overarching aim of management is to minimise and prevent the health consequences of hypogonadism, such as sexual symptoms, low mood, tiredness, anaemia, and reduced bone mineralisation.
Testosterone therapy
Recommended for most men with hypogonadism.
Three specific subsets of hypogonadism should not routinely be treated with testosterone therapy:
Hypogonadism due to non-gonadal illness (NGI)
Hypogonadism due to prolactinoma
Secondary hypogonadism in men who currently desire fertility.
Testosterone therapy is not recommended for men without a clinical diagnosis of hypogonadism (e.g., for sexual dysfunction without testosterone deficiency or male ageing).[1][39][40]
Testosterone therapy effect and routes of administration
The class effect of testosterone therapy, compared with placebo, is to improve libido, erectile function, quality of life, depression, bone mineral density, and alleviate anaemia if present.[41] The therapeutic aim is to achieve physiological testosterone levels, usually to the mid-normal range, and to reverse hypogonadal symptoms and signs.
The adequacy of testosterone therapy is assessed by clinical symptoms and serum testosterone levels.[1][27] Patients require regular follow-up to ensure compliance, assess effectiveness, adjust dosing, and monitor for adverse effects. Patients should be reviewed at regular intervals (every 3 to 4 months) during the first year of treatment, and annually thereafter.[28][34] Haematocrit should also be checked at these visits.
Topical and transdermal testosterone formulations
The choice of specific type of testosterone and route of testosterone administration should be informed by shared decision-making and guided by efficacy, patient preference, ease of use, and safety.[42] Availability of testosterone formulations may differ between countries.
Formulations include gels, solution, and transdermal patch (in some countries); these require once-daily application. Testosterone levels can be checked to see if they have reached therapeutic levels after 1 week of using transdermal products. Physiological serum levels can be achieved with dose adjustment. Testosterone level should be measured 2 to 4 hours after gel application as this gives the peak value.
Transfer of testosterone from patient to partner or child through skin-to-skin contact has been reported in patients using gel or cream preparations, but is extremely rare. This can be avoided by washing hands after application, and covering treated skin areas with clothing.[42]
Intramuscular testosterone
A long-acting intramuscular formulation (testosterone undecanoate) can be given every 8-12 weeks to maintain testosterone levels within the normal physiological range. Testosterone levels should be measured immediately prior to an injection (i.e., trough level) to ensure concentration is near the low-normal range. If the patient experiences a return or persistence of symptoms and testosterone is low once established on therapy, then injection frequency can be increased (as the dose cannot be changed). If trough testosterone is greater than mid-normal range, injection frequency should be reduced. Peak or post-injection levels should also be considered in men without symptomatic improvement.
Short-acting forms of injectable testosterone include esters such as testosterone cipionate and testosterone enantate. Formulations with a mixture of testosterone salts may be available in some countries. Short-acting injectable formulations are normally administered every 1-4 weeks (depending on the formulation); dose interval may need to be adjusted to achieve therapeutic effect without adverse effects.
Serum testosterone levels achieved with short-acting intramuscular injections of testosterone are highly variable due to medication decay. Immediately after injection, supraphysiological levels may occur. Levels then decline, reaching near hypogonadal levels after 2 weeks post-injection. For this reason, it is seldom useful to measure peak levels of testosterone after an injection. Rather, trough levels (prior to the next injection) are more helpful.
All intramuscular preparations of testosterone should be warmed to body temperature and administered slowly to reduce discomfort. Long-acting intramuscular testosterone undecanoate should be administered over 60 to 90 seconds to reduce injection pain and the risk of pulmonary oil microembolism (POME). Patients who receive testosterone undecanoate should be monitored for 30 minutes after injection in the clinic for clinical symptoms of embolisation, such as cough or chest pain.
Erythrocytosis and gynaecomastia (due to high oestradiol levels resulting from aromatisation of testosterone) occur more commonly with intramuscular injections than with transdermal preparations.
Food-based oils are used as a vehicle to deliver many testosterone esters, so any patient allergies should be checked before use.
Intranasal testosterone gel
After blowing the nose, the dose is applied to the inside of each nostril. Most patients achieve normal physiological range testosterone levels.
Subcutaneous testosterone
Clinicians should consider discussing the use of subcutaneous testosterone enantate with patients. Self-administration is relatively easy, potentially improving patient adherence.[43]
Oral testosterone
Oral testosterone undecanoate is an equivalent alternative to testosterone gel with minimal adverse effects, ease of use, and higher patient compliance.
Contraindications, adverse effects, and monitoring of testosterone therapy
Contraindications to testosterone therapy include unmonitored prostate or breast cancer; untreated, uncontrolled, or severe congestive cardiac failure; untreated, uncontrolled, or severe obstructive sleep apnoea; untreated, severe lower urinary tract symptoms associated with benign prostatic hypertrophy; and untreated sleep apnoea.[34]
Changes in lower urinary tract symptoms should be monitored, particularly in middle-aged and older men recently initiated on testosterone therapy. This is because the prostate physiologically grows slightly when hypogonadal testosterone levels are restored to normal circulating levels. While there is no evidence to indicate that testosterone therapy causes prostate cancer, testosterone therapy can unmask a prostate cancer that was not evident prior to starting treatment, or it may aggravate pre-existing prostate cancer. The US Endocrine Society recommends regular prostate-specific antigen and digital rectal examinations for men receiving testosterone therapy.[34] However, the accuracy or safety of this screening approach is not known. The UK Society for Endocrinology guidelines no longer mandate specific prostate screening during testosterone therapy.[2] Rather, men should receive standard prostate screening if available nationally. If no national screening is available, clinicians should be vigilant for new lower urinary tract symptoms, particularly in men with risk factors for prostate cancer (age over 60 years, black ethnicity, family history of prostate cancer). Such symptoms require investigation by a urologist.
Testosterone therapy can be considered in men successfully treated for breast or prostate cancer after a prudent interval with no evidence of residual cancer confirmed by the specialist managing the cancer. Agreement to consider testosterone therapy should be sought from the specialist. The risks and benefits of testosterone therapy must be discussed with the patient. Treatment would only be considered in patients who have symptoms that are significantly affecting their quality of life. Strict follow-up of these patients is particularly important.[27][28]
Cardiovascular risk
Controversy exists regarding the effect of testosterone therapy on cardiovascular risk. Several studies have reported increased risk of adverse cardiovascular events following testosterone therapy; however, others suggest that testosterone therapy may have no effect, or even reduce the risks of cardiovascular events.[44][45][46]
In one large randomised controlled trial of testosterone replacement therapy in men with hypogonadism and pre-existing or a high risk of cardiovascular disease, there was no increase in adverse major cardiac events in the testosterone group.[47]
One meta-analysis of randomised controlled trials suggested that testosterone replacement therapy is not associated with increased risk of venous thromboembolism (VTE); however, the quality of evidence was low.[48]
Data from one large observational study indicated that testosterone treatment was associated with a twofold increased risk of VTE compared with non-treatment.[49] Obese men were at higher risk of VTE in this study, and the highest overall risk was observed during the first 6 months of treatment.
Testosterone therapy has little effect on serum fasting lipids or blood pressure.[34][50][51][52] In addition, testosterone therapy has been shown to have beneficial effects on insulin resistance and reduces progression of pre-diabetes to diabetes in men with metabolic syndrome undergoing weight loss.[53]
The US Food and Drug Administration (FDA) recommends that men on testosterone treatment be advised of the potential cardiovascular risks.[54] The European Medicines Agency (EMA) has previously reported that there is no consistent evidence of increased cardiovascular risk with testosterone therapy.[55]
Counsel patients and adopt risk minimisation measures
Clinicians should consider cardiovascular risk in men before initiating testosterone treatment. In men with high cardiovascular risk, counselling regarding the uncertainty of the cardiovascular safety of testosterone therapy is recommended. Where the clinical benefits of testosterone are clear (e.g., severe or highly symptomatic hypogonadism), then the potential risks of testosterone treatment are likely to be worth taking. Decisions need to be agreed jointly with the patient.
Clinicians should counsel men that testosterone treatment can increase thrombosis risk, although the absolute risk is low and can be minimised by ensuring that haematocrit remains in the reference range. When haematocrit is elevated >0.5, lower the dose of daily transdermal testosterone treatment, or extend the interval between testosterone injections.
Transdermal testosterone treatment has a lower risk of erythrocytosis compared with injectable testosterone treatment, so consider switching to gels in men with high haematocrit while on testosterone injections.[56] Secondary causes of elevated haematocrit should be investigated. Stop testosterone treatment and seek urgent haematological advice when haematocrit remains markedly elevated despite the measures described.
Inform patients that all formulations of testosterone therapy can cause polycythaemia, oily skin, and acne.
Pulmonary oil microembolism (POME)
POME may occur with intramuscular injections of long-acting testosterone undecanoate, and less commonly with other oil-based intramuscular testosterone injections. Symptoms may include cough, dyspnoea, throat tightening, chest pain, dizziness, and syncope.[57] These episodes typically occur within 30 minutes of administration and resolve spontaneously. POME is much less frequent if the injection is given slowly. For this reason, long-acting testosterone undecanoate should be administered in a healthcare setting (rather than at home).
Men with hypogonadism not routinely treated with testosterone
There are three specific subsets of men with hypogonadism who should not routinely be treated with testosterone therapy.
Hypogonadism due to non-gonadal illness (NGI)
These patients should receive treatment of the underlying cause. For instance, obesity is a common cause of hypogonadism, which may be reversed by lifestyle intervention. See Obesity in adults.
When NGI cannot be reversed, testosterone therapy may be considered.
Hypogonadism due to prolactinoma (microadenoma or macroadenoma)
A dopamine agonist, such as cabergoline or bromocriptine, is first-line treatment.[58] Patients should be referred to an endocrinologist for management, which will include magnetic resonance imaging (MRI) of the pituitary gland, and visual field assessment (due to the association with bitemporal hemianopia in prolactin-secreting macroadenomas). See Prolactinoma.
Testosterone therapy can be initiated to improve symptoms of hypogonadism in the small percentage of patients who do not respond to a dopamine agonist.
Surgery is considered when the patient is resistant to, or intolerant of, dopamine agonists, or has recurrent tumour after dopamine agonist withdrawal. Preferred surgical candidates include those patients with enclosed microadenoma.[59] Surgery is less preferred for patients with an invasive prolactinoma because postoperative remission rates are less favourable.[60] Surgery itself may cause damage to normal pituitary tissue; the decision to perform surgery should take into account surgeon experience and possibility of complications. Surgery, as with dopamine agonist therapy, may lead to some reversal of the hypogonadism.
Men with secondary hypogonadism who currently desire fertility
Exogenous testosterone therapy will suppress luteinising hormone (LH) and follicle stimulating hormone (FSH), and temporarily inhibit spermatogenesis. However, prior testosterone therapy does not significantly impair future semen quality in men with hypogonadism.[61]
Patients should be reassured that testosterone therapy is suitable and safe for men to take until they are approximately 1-2 years from wishing to conceive with their partner. Once men want to conceive, they may be switched from testosterone to human chorionic gonadotrophin (alone or in combination with FSH) to stimulate spermatogenesis in the testes and secretion of endogenous testosterone.[62] Pulsatile gonadotrophin-releasing hormone therapy is seldom available outside the research setting.
A selective oestrogen receptor modulator (SERM) such as clomifene or tamoxifen, or an aromatase inhibitor such as anastrozole, are off-label alternatives to gonadotrophins that may be considered by a specialist. They are only suitable when pituitary function is intact.[63]
Assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) involve the administration of hormonal treatment to the female partner to stimulate ovarian follicle growth. Eggs are collected, fertilised, then reimplanted in the uterus.
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