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:
Low testosterone levels due to non-gonadal illness (without relevant clinical features)
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 normal male ageing).[1][51][52]
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.[53]
The therapeutic aim is to reverse hypogonadal symptoms and signs, and achieve physiological testosterone levels in the mid-normal range (subject to maintaining normal haemoglobin and haematocrit).
The adequacy of testosterone therapy is assessed by clinical symptoms, serum testosterone levels, and relevant biomarkers such as haematocrit and bone density.[28][54]
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 3-4 months) during the first year of treatment, and annually thereafter.[29][37] Dose titration or adjustment of injection frequency may be required to attain adequate circulating testosterone levels and to maintain normal haematocrit.
The choice of testosterone formulation and route of administration should be informed by shared decision-making and guided by efficacy, patient preference, ease of use, and safety.[54] Availability of testosterone formulations may differ between countries.
Topical and transdermal testosterone formulations
Formulations include gels, solution, and (in some countries) patches; 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; haematocrit will take approximately 2 months to reach a steady state. Physiological serum levels can be achieved with dose adjustment. Testosterone level should be measured 6-12 hours after gel application as this gives the mid-point 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.[54]
Intramuscular testosterone
A long-acting intramuscular formulation (testosterone undecanoate) can be given every 10-16 weeks to maintain testosterone levels within the normal physiological range. Testosterone levels should be measured either immediately prior to an injection (i.e., trough level) to ensure concentration is near the low-normal range, or at the mid-point between injections, aiming for a mid-range testosterone concentration.
Short-acting forms of intramuscular testosterone include esters such as testosterone cipionate and testosterone enantate. Formulations with a mixture of testosterone esters may be available in some countries. Short-acting injectable formulations are normally administered every 2-4 weeks (depending on the formulation).
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 at 2 weeks post-injection. For this reason, trough levels should be measured.
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 60-90 seconds to reduce injection pain and the risk of pulmonary oil microembolism (POME). Patients who receive long-acting intramuscular testosterone undecanoate should be monitored for 30 minutes after injection in the clinic for clinical symptoms of embolisation, such as cough or chest pain.[54] See Complications.
Erythrocytosis and gynaecomastia 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 using a metered-dose pump. Most patients achieve normal physiological range testosterone levels.
Subcutaneous testosterone injection devices
Clinicians should consider discussing the use of subcutaneous testosterone enantate with patients, where available. Self-administration is relatively easy, potentially improving patient adherence.[55]
Oral testosterone undecanoate
An equivalent alternative to testosterone gel with minimal adverse effects (transient liver enzyme elevation, but without the liver toxicity associated with methyltestosterone-based oral formulations), ease of use, and high patient compliance.[56][57][58]
Testosterone pellet implants
Long-acting testosterone pellets for subcutaneous implantation may be an option. Implants last up to 6 months, depending on the number of pellets used. Patients require monitoring to determine how many pellets should be implanted to maintain testosterone levels.[54][59] Implantation is invasive and extrusions can occur.[54]
Contraindications, adverse effects, and monitoring of testosterone therapy
Contraindications to testosterone therapy include:[37]
a past history of breast cancer;
prostate cancer within 2 years (the usual recommended period of androgen suppression) or that could not be treated with curative intent;
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
elevated haematocrit >50%.
Prostate risk
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. One large randomised controlled trial failed to observe a significant difference in incidence of prostate cancer, or other prostate-related events, in men taking testosterone therapy compared with placebo (mean treatment duration 22 months).[60]
The US Endocrine Society recommends regular prostate-specific antigen and digital rectal examinations for men receiving testosterone therapy.[37] 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 recommended, 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, BRCA mutation). 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. Treatment would only be considered in patients with pathological hypogonadism and relevant symptoms or signs; risks and benefits of testosterone therapy must be discussed with the patient. Strict follow-up of these patients is particularly important.[28][29]
Cardiovascular risk
Although previously controversial, high-quality evidence suggests that testosterone therapy (over 1-4 years of treatment) does not increase cardiovascular risk in men with hypogonadism.[62][63][65][61]
One meta-analysis of individual participant data from placebo-controlled randomised controlled trials found no evidence that testosterone therapy increased short-term to medium-term cardiovascular risks of any subtype in men with hypogonadism.[62][63] Long-term studies are lacking.
Evidence for an effect on blood pressure is inconsistent; however, small increases have been reported in patients receiving various formulations of testosterone, including oral testosterone undecanoate and subcutaneous injections.[56][62][61][66][67]
The Food and Drug Administration (FDA) has updated its safety information for all testosterone products, requiring labelling changes including the removal of a warning stating that testosterone therapy increases the risk of major adverse cardiovascular outcomes. New information has been added about the risk of increased blood pressure, based on the findings of postmarketing ambulatory blood pressure studies.[64] The European Medicines Agency (EMA) has previously reported that there is no consistent evidence of increased cardiovascular risk with testosterone therapy.[68]
Testosterone therapy may increase haematocrit; however, most studies do not report an increase in venous thromboembolism risk.[62][69]
Assess cardiovascular risk factors before starting testosterone therapy, and check blood pressure and haematocrit regularly during treatment. In most patients (without increased risk of cardiovascular disease), elevated haematocrit may be managed by reducing testosterone dose, and/or changing the formulation (e.g., from an intramuscular to a transdermal preparation). Phlebotomy is not recommended except under exceptional circumstances due to a lack of evidence of benefit.[2][70]
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.
Low testosterone levels due to non-gonadal illness (NGI)
Men with physiologically suppressed gonadotrophins and testosterone concentrations due to NGI should receive treatment of the underlying cause. For instance, obesity is a common cause of NGI, 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.[71] 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).
Inform patients of the risk of rare but devastating psychiatric adverse effects with dopamine agonists, such as impulse control disorders.[72] 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, or as a bridging treatment to relieve symptoms until the dopamine agonist takes effect.
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.[73] Surgery is less preferred for patients with an invasive prolactinoma because postoperative remission rates are less favourable.[74] 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 congenital hypogonadotrophic hypogonadism.[75]
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.[76] Treatment may need to be continued for up to 2 years. Pulsatile gonadotrophin-releasing hormone therapy is seldom available outside the research setting.
Patients with adult-onset secondary hypogonadism may achieve restoration of spermatogenesis and fertility with human chorionic gonadotrophin (hCG) monotherapy. If hCG monotherapy is unsuccessful, FSH may be added. Those with combined pituitary hormone deficiency or congenital hypogonadotrophic hypogonadism, will need hCG combined with FSH.
Techniques 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 (embryo transfer) into the uterus.
Surgical sperm retrieval, particularly microdissection testicular sperm extraction (micro-TESE), is an option to extract viable sperm for IVF/ICSI in men with hypogonadism and azoospermia. See Male factor infertility.
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