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British Society for Sexual Medicine guidelines on adult testosterone deficiency, with statements for UK practice

  • It is the editorial policy of Guidelines not to use proprietary drug names, however, an exception has been made in this case to aid differentiation between multiple formulations containing the same drug  

Clinical diagnosis of testosterone deficiency

  • The diagnosis of symptomatic testosterone deficiency (TD) requires the presence of characteristic signs and symptoms plus decreased serum concentrations of total testosterone (TT) or free testosterone (FT)
  • The assessment of gonadotropins is required to determine the origin of the TD

Signs, symptoms, and comorbidities

  • TD has well established symptoms. The 4th International Consultation for Sexual Medicine (ICSM) made the following recommendations for the clinical diagnosis of TD based on the following signs and symptoms:
    • sexual dysfunction, especially low sexual desire, decreased morning and night-time erections, and erectile dysfunction (ED) are prominent, commonly presenting symptoms particularly suggestive of TD when associated with each other
    • less specific symptoms such as fatigue, sleep disturbance, loss of physical strength, decreased energy and motivation, and depressed mood are often present
    • visceral obesity and decreases in muscle mass and bone mineral density are commonly observed
    • hot flushes and changes in cognition and memory can be associated with TD
    • on physical examination, features suggestive of TD include decreased body hair, decreased testicular size, and gynecomastia, but these are not always present. Fine wrinkling of the skin, especially around the mouth, also can be apparent

Clinical signs and symptoms suggestive of TD*

  • Sexual:
    • delayed puberty
    • small testes
    • infertility
    • decreased sexual desire and activity
    • decreased frequency of sexual thoughts
    • erectile dysfunction
    • delayed ejaculation
    • decreased volume of ejaculate
    • decreased or absent morning or night-time erections
  • Cardiometabolic:
    • increased body-mass index (BMI) or obesity
    • visceral obesity
    • metabolic syndrome
    • insulin resistance and type 2 diabetes mellitus (T2DM)
  • Physical:
    • decreased body hair
    • gynecomastia
    • decreased muscle mass and strength
    • hot flushes or sweats
    • sleep disturbances
    • fatigue
    • osteoporosis, height loss, low trauma fractures
  • Psychological:
    • changes in mood (e.g., anger, irritability, sadness, depression)
    • decreased well-being or poor self-rated health
    • decreased cognitive function (including impaired concentration, verbal memory, and spatial performance)

* TD is often associated with increased waist circumference, obesity, metabolic syndrome, and impaired health status. In a primary care population of men at least 45 years, the reported odds ratios for TD with comorbid conditions were 2.38 for obesity, 2.09 for T2DM, 1.84 for hypertension, 1.47 for dyslipidemia, 1.40 for chronic obstructive pulmonary disease, and 1.20 for lower urinary tract symptoms related to benign prostatic hyperplasia. Significant TD is associated with an increased risk of chronic anemia and osteoporosis.

Factors associated with an increased prevalence of TD

  • Andrologic and endocrinologic:
    • delayed puberty
    • cryptorchidism
    • pituitary disease
    • infertility
    • varicocele
  • Metabolic diseases associated with insulin resistance:
    • obesity
    • metabolic syndrome
    • type 2 diabetes
  • Cardiovascular diseases:
    • hypertension
    • coronary artery disease
    • cerebrovascular disease
    • chronic heart failure
    • atrial fibrillation
  • Other chronic disease:
    • chronic obstructive pulmonary disease
    • obstructive sleep apnea
    • end-stage renal disease
    • cirrhosis
    • osteoporosis
    • rheumatoid arthritis
    • HIV
    • cancer
  • Pharmacologic:
    • oral glucocorticoid treatment
    • regular opioid use
    • antipsychotic medications
    • androgen deprivation therapy
    • methadone maintenance therapy
    • antiretroviral therapy
    • chemotherapy plus radiation
    • anticonvulsant therapy

Screening

  • Screen for TD in adult men with consistent and multiple signs of TD
  • Screen all men presenting with ED, loss of spontaneous erections, or low sexual desire
  • Screen for TD in all men with T2DM, BMI >30 kg/m2 or waist circumference >102 cm
  • Screen for TD in all men on long-term opiate, antipsychotic, or anticonvulsation medication

Diagnosis

  • Restrict diagnosis of TD to men with persistent symptoms suggesting TD and confirmed low testosterone
  • Measure fasting testosterone levels in the morning before 11 AM, acknowledging that, in normal life, non-fasting levels could be up to 30% lower
  • Repeat TT assessment on ≥2 occasions by a reliable method; in addition, measure FT in men with levels close to the lower normal range (8–12 nmol/l) or those with suspected or known abnormal sex hormone-binding globulin (SHBG) levels
  • Measure LH serum levels to differentiate primary from secondary TD
  • Base decisions on therapy on published action levels rather than laboratory reference ranges

Thresholds for testosterone therapy

  • Regarding the thresholds for treatment intervention in symptomatic men, British Society for Sexual Medicine (BSSM) and International Society for Sexual Medicine (ISSM) guidelines recommend the following:
    • TT level lower than 8 nmol/l or FT level lower than 180 pmol/l (<0.180 nmol/l; based on 2 separate levels from 8 to 11 AM) usually requires testosterone therapy
    • TT level higher than 12 nmol/l or FT level higher than 225 pmol/l (>0.225 nmol/l) does not require testosterone therapy
    • levels from 8 to 12 nmol/l might require a trial of testosterone therapy for a minimum of 6 months based on symptoms
  • BSSM guidelines also state:
    • a FT level lower than 225 pmol/l (0.225 nmol/l) provides supportive evidence for testosterone therapy in the presence of appropriate symptoms
  • Additional recommendations include:
    • increased luteinising hormone (LH) levels and testosterone levels below normal or in the lower quartile range indicate testicular failure, so testosterone therapy should be considered
    • increased LH levels in men with normal testosterone levels but symptoms of TD should be considered as having TD
    • recent data from the EMAS found that clinical symptoms were more closely related to calculated FT

Initiating testosterone therapy

  • Perform cardiovascular (CV), prostate, breast, and hematologic assessments before start of treatment
  • Offer testosterone therapy to symptomatic men with TD syndrome for treated localised low-risk prostate cancer (Gleason score <8, stages 1–2, preoperative prostate-specific antigen (PSA) level <10 ng/mL, and not starting before 1 year of follow-up) and without evidence of active disease (based on measurable PSA level, digital rectal examination (DRE) result, and evidence of metastatic disease)
  • Assess CV risk factors before commencing testosterone therapy and optimise secondary prevention in men with established disease
Table 1: Testosterone therapy options
FormulationRoute of administration Frequency of administrationAdvantagesDisadvantages 

Testosterone 1% and 2% gel available

Transdermal gel

Applied daily, requires dose titration

Fast onset; provide uniform and normal serum levels for 24 hours

Skin irritation at application site

Potential for interpersonal transfer

Non-compliance long term 

Testosterone undecanoate

Oral capsules

Once or twice daily

Lymphatic absorption decrease liver involvement

Levels fluctuate

Daily or twice-daily commitment

Must be taken with food

Testosterone undecanoate

Intramuscular injection 

Every 10–14 weeks adjusted to maintain trough testosterone level >12 nmol/l

Steady-state levels

Lower frequency of administration improves compliance

Long duration of action prevents drug withdrawal in the event of adverse side effects

Testosterone enanthate

Intramuscular injection 

Every 2–3 weeks

Short duration of action allows drug withdrawal if there are adverse side effects

Levels fluctuate

Testosterone propionate

Intramuscular injection 

Currently available as 1 of 4 testosterone esters used in sustanon 250, which is usually administered every 3 weeks; sustanon’s duration of action prevents drug withdrawal in the event of adverse side effects

It is the editorial policy of Guidelines not to use proprietary drug names, however, an exception has been made in this case to aid differentiation between multiple formulations containing the same drug

Benefits and risks of testosterone therapy

  • Beyond 6 months there is evidence of benefit for testosterone therapy in body composition, bone mineralisation, and features of metabolic syndrome
  • Testosterone therapy improves sexual desire, erectile function, and sexual satisfaction
  • Decreases in BMI and waist size and improved glycemic control and lipid profile are observed in hypogonadal men receiving testosterone therapy
  • Trials of testosterone therapy should be ≥6 months and maximal benefit is often seen beyond 12 months
  • Fully inform the patient about expected benefits and side effects of therapy and facilitate a joint decision by an informed patient and physician
  • Fully discuss the adverse effect of testosterone therapy and its future reversibility on future fertility for each patient and his partner and offer alternative treatment as necessary
  • In patients with adult-onset TD, when testosterone replacement therapy is prescribed, offer weight-loss and lifestyle advice as standard management
  • In severely symptomatic patients with TT levels <8 nmol/l, lifestyle and dietary advice alone is unlikely to produce meaningful clinical improvement within a relevant clinical period

Follow-up

  • Assess the response to therapy at 3, 6, and 12 months and every 12 months thereafter
  • Aim for a target TT level of 15–30 nmol/l to achieve optimal response
  • Monitor hematocrit before treatment, at 3–6 months, 12 months, and every 12 months thereafter; decrease dosage, or switch preparation, if hematocrit is >0.54; if hematocrit remains high, consider stopping and reintroduce at lower dose
  • Assess prostate health by PSA assessment and DRE before commencing testosterone replacement therapy followed by PSA at 3–6 months, 12 months, and every 12 months thereafter
  • Assess CV risk before testosterone replacement therapy is initiated and monitor CV risk factors throughout therapy

* TD is often associated with increased waist circumference, obesity, metabolic syndrome, and impaired health status. In a primary care population of men at least 45 years, the reported odds ratios for TD with comorbid conditions were 2.38 for obesity, 2.09 for T2DM, 1.84 for hypertension, 1.47 for dyslipidemia, 1.40 for chronic obstructive pulmonary disease, and 1.20 for lower urinary tract symptoms related to benign prostatic hyperplasia. Significant TD is associated with an increased risk of chronic anemia and osteoporosis.

full guideline available from…

British Society for Sexual Medicine, Holly Cottage, Fisherwick, Near Lichfield, Staffordshire WS14 9JL (Tel – 01543 432622) 

http://www.bssm.org.uk/wp-content/uploads/2017/12/guidelines-on-adult-testosterone-deficiency-with-statements-for-uk-practice.pdf

Hackett G, Kirby M, Edwards D et al. British Society for Sexual Medicine Guidelines on adult testosterone deficiency, with statements for UK practice. J Sex Med 2017; 14: 1504–1523.

First included: January 2018.