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SatuVehkavaara

Male Hypogonadism and Hormone Replacement

Essentials

  • Primary and secondary hypogonadism must be differentiated from each other.
  • Treatment decisions should always be based on at least two measurements obtained by reliable measuring methods and considered together with the symptoms.
  • In primary and secondary organic hypogonadism, testosterone replacement therapy is started, unless it is contraindicated. In secondary functional hypogonadism, treatment according to the aetiology is essential.
  • Starting testosterone therapy to elderly men should be carefully weighed up.

Regulation of male sex hormone levels

  • Luteinising hormone (LH) stimulates the production of testosterone in the Leydig cells.
  • Follicle-stimulating hormone (FSH) stimulates the function of testicular Sertoli cells, which have an important role in the production of spermatozoa.

Symptoms of hypogonadism (testosterone deficiency)

  • The onset of hypogonadism before puberty results in delayed pubertal development and abnormalities in pubertal screening. However, the most common cause of delayed pubertal development is idiopathic delayed puberty Pubertal Development and its Disturbances.
  • In adulthood, the most obvious symptoms associated with testosterone deficiency are
  • Other, less specific symptoms may include
    • loss of hair growth
    • hot flushes and sweating
    • gynaecomastia
    • osteoporosis
    • infertility
    • normocytic anaemia
    • increased fat to muscle mass ratio
    • fatigue and problems with concentration and mood.

Main causes of hypogonadism

  • Table T1 shows the main causes of hypogonadism, with a breakdown.
  • The cause of hypogonadism should always be determined before starting testosterone therapy, as whatever the cause, the LH level measured during therapy is always unmeasurably low.
  • In functional hypogonadism, treatment according to the aetiology is always the first priority.
    • In obesity, significant weight loss not only corrects the manifestations of the metabolic syndrome but also increases testosterone levels.
    • If hyperprolactinemia is detected and drugs affecting the pituitary-testicular axis via hyperprolactinemia (e.g. antipsychotics, metoclopramide) are in use, these should be discontinued or switched to another product, as far as possible.
      • If no obvious cause for hyperprolactinemia is available, prolactinoma should be excluded by MRI of the sella turcica.
    • Other known classes of drugs that lower testosterone levels include opioids, glucocorticoids and anabolic steroids Steroid Doping.
    • Heavy alcohol consumption and cannabis use may also contribute to lower testosterone levels.

Classification of hypogonadism

Primary (testicular)Secondary (central i.e. disturbances in the regulation of the hypothalamic-pituitary-testicular axis)
Organic
  • Klinefelter's syndrome Klinefelter's Syndrome
  • Cryptorchidism Undescended Testicle, anorchia
  • Cancer drugs, radiation-induced testicular injury or status post-orchiectomy
  • Orchitis, testicular injury or torsion
  • Impact of aging on testis
  • Hypothalamic or pituitary tumours Pituitary Tumours
  • Hemochromatosis Haemochromatosis
  • Infiltrating or destructive diseases of the hypothalamus or pituitary gland
  • Idiopathic hypogonadotropic hypogonadism
Functional
  • Hyperprolactinaemia
  • Opioids, anabolic steroids Steroid Doping, glucocorticoids
  • Heavy alcohol use, marijuana use*
  • Systemic diseases*
  • Malnutrition or overtraining syndrome
  • Obesity Raising the Subject of Obesity, and Assessment of Obesity, sleep apnoea Sleep Apnoea in the Adult
  • Severe disease of the liver, heart or lungs*
* Combined primary and secondary hypogonadism
Modified from source: Finnish Medical Journal Duodecim 2020;136(2):129-3716.
Investigations
  • Serum total testosterone is measured and further investigations are determined by its concentration, see Figure 1 in http://onlinelibrary.wiley.com/doi/10.1111/andr.12770.
    • Normally only 2% of circulating testosterone is in a biologically active form, i.e. free, and the rest is bound to SHBG.
    • The sample should be collected in the morning, preferably between 7 and 10 (AM).
  • If serum testosterone is at the lower end of the reference range and
    • SHBG is low, free testosterone is normal
    • SHBG is high, free testosterone is low.
  • The diagnosis of hypogonadism may not be straightforward as the level of testosterone even in a healthy man shows some fluctuation.
    • For example, strenuous exercise, malnutrition and stress of various origin (for example, surgery) will temporary lower the level.
    • Neither is diagnosis of hypogonadism helped by the fact that symptoms suggestive of hypogonadism are found in up to a third of fully eugonadal men.
  • Testosterone concentration should be determined by a reliable immunological method or by liquid chromatography-mass spectrometry (LC-MS).
  • If serum testosterone is < 8 nmol/l, the patient has hypogonadism and its cause must be identified.
    • Serum testosterone concentration between 8 and 12 nmol/l is a grey area, i.e. some of the patients will have true hypogonadism but some will have a low result due to any of the aforementioned temporary causes or their SHBG concentration is low.
    • Because of this reason, serum testosterone should be determined several times before treatment decisions are made or larger investigations carried out.
    • In borderline cases, it may be useful to assess calculated free testosterone concentration.
  • Further investigation of hypogonadism includes measurement of gonadotropin levels: luteinizing hormone (LH), and, as considered necessary, follicle-stimulating hormone (FSH).
    • Increased levels suggest a primary testicular cause and decreased or normal levels suggest a secondary cause.
  • In primary hypogonadism in young men, chromosome analysis is performed if Klinefelter's syndrome is suspected (in specialized care).
  • In cases of secondary hypogonadism, hyperprolactinaemia should be excluded and, if considered necessary, the other pituitary gland hormones are determined and an MRI of the sellar region is carried out (if serum testosterone < 6 nmol/l).

Treatment

  • Testosterone replacement therapy for both primary and secondary organic hypogonadism.
  • For secondary functional hypogonadism, treatment according to the aetiology (e.g. treatment of obesity and metabolic syndrome, cessation of opioids and anabolic steroids) is essential.
    • Anabolic steroid-induced hypogonadism (ASIH) resolves in the majority of cases within months of cessation. When monitoring ASIH, in addition to testosterone levels, LH rises to reference values as a sign of recovery of the pituitary-testicular axis.
  • Starting treatment should be carefully considered in older men and in men with a haematocrit already close to the upper limit of the reference range (> 46%) at baseline.

Testosterone replacement therapy

  • Intramuscular testosterone undecanoate every 10 to 14 weeks.
    • Provides more even and longer lasting levels than testosterone esters.
    • The target is serum testosterone concentration of 15-25 nmol/l measured in the middle of the period between injections and concentration at the lower limit of reference range measured right before the next injection.
  • Intramuscular testosterone esters every 2 to 4 weeks
    • The patient's subjective feeling of well-being is the best indicator of suitable dosing interval.
  • Testosterone gels once daily (preferably in the morning).
    • The dose is adjusted on the basis of serum testosterone level and symptoms of androgen deficiency.

Monitoring testosterone replacement therapy

  • Testosterone replacement therapy involves monitoring blood count (haematocrit; polycythaemia) and testosterone levels initially every 3-6 months and then annually.
  • For patients over 40 years of age, PSA concentration, prostate size (digital rectal examination, DRE) and, as considered necessary, plasma lipid and liver values are also monitored.
  • If, at follow-up, haematocrit rises above 52%, treatment should be paused until haematocrit is within reference values and, depending on the treatment regimen, either the interval between injections should be made longer (injectable treatment) or the dose should be reduced (gels). A switch from injection therapy to gel therapy may be attempted.
  • Consultation of a urologist is necessary if PSA rises above the reference value or if an abnormal prostate finding is detected (DRE/ultrasound examination).

Contraindications to testosterone treatment

  • Prostate cancer, breast cancer
  • Untreated prostatic hyperplasia causing bladder outlet obstruction, or increased PSA concentration before the treatment or increasing during it
  • Polycythaemia
  • Severe sleep apnoea
  • Decompensated heart failure
  • Desire to have a child in the near future

Hypogonadism in elderly men

  • The functioning of the testes declines with advancing age, but in most aging men compensatory increases in gonadotrophin secretion maintain testicular functioning near normal.
  • A small proportion of men develop hypogonadism, which in these cases is known as late-onset hypogonadism (LOH). Serum testosterone levels are usually only slightly reduced.
  • LOH reflects the general health status of an aging man. Aetiological factors more important than the biological age are obesity, general health and medication in use. Treatment should therefore principally target underlying factors, such as the management of obesity and cardiovascular risk factors.
  • The need for testosterone therapy in LOH is debatable. The lower the testosterone level, the more likely testosterone therapy is to be of benefit. Concentration below 7-8 nmol/l is abnormal and if this is combined with symptoms matching hypogonadism, at least a therapeutic trial may be regarded as indicated. If no benefit is gained, treatment should be stopped.
  • If the patient is obese, the first-line treatment approach is weight loss and the management of any medical disorders associated with metabolic syndrome Metabolic Syndrome. In men with clear overweight (BMI over 30 kg/m2 ) the testosterone concentration is in all age groups 4-5 nmol/l lower than in men with normal weight. Weight loss will increase the concentration.
  • Monitoring during testosterone therapy: see above Testosterone replacement therapy. The monitoring of elderly men must pay particular attention to prostate specific symptoms.

Division of labour between specialized and primary care

  • Basic investigations and level diagnosis of hypogonadism are carried out in primary care.
  • Investigations of primary and secondary hypogonadism in young men are carried out in specialized care if there is no clear underlying cause (e.g. use of anabolic steroids Steroid Doping).
  • Treatment and monitoring of evident secondary functional hypogonadism is carried out in primary care.
  • If there is suspicion of secondary organic hypogonadism or if there are differential diagnostic problems in the diagnosis of organic and functional hypogonadism, consultation of a specialist clinic about the need for MRI of the sella turcica is warranted.
  • Find out about local policies and practices concerning the roles of primary and secondary care.

    References

    • Bhasin S, Brito JP, Cunningham GR ym. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2018;103(5):1715-1744. [PubMed]
    • Travison TG, Vesper HW, Orwoll E ym. Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe. J Clin Endocrinol Metab 2017;102(4):1161-1173. [PubMed]
    • Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N ym. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: A systematic review and meta-analysis of randomized, placebo-controlled trials. J Clin Endocrinol Metab 2018;103(5):1745-1754. [PubMed]
    • Cunningham GR, Stephens-Shields AJ, Rosen RC ym. Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. J Clin Endocrinol Metab 2016;101(8):3096-3104. [PubMed]
    • Snyder PJ, Kopperdahl DL, Stephens-Shields AJ ym. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med 2017;177(4):471-479. [PubMed]
    • Cheetham TC, An J, Jacobsen SJ ym. Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA Intern Med 2017;177(4):491-499. [PubMed]
    • Alexander GC, Iyer G, Lucas E ym. Cardiovascular Risks of Exogenous Testosterone Use Among Men: A Systematic Review and Meta-Analysis. Am J Med 2017;130(3):293-305. [PubMed]
    • Budoff MJ, Ellenberg SS, Lewis CE ym. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA 2017;317(7):708-716. [PubMed]
    • Snyder PJ, Bhasin S, Cunningham GR et al. Effects of Testosterone Treatment in Older Men. N Engl J Med 2016;374(7):611-24. [PubMed]
    • Yeap BB, Alfonso H, Chubb SA et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014;99(1):E9-18. [PubMed]
    • Wu FC, Tajar A, Beynon JM et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363(2):123-35. [PubMed]
    • Spitzer M, Huang G, Basaria S et al. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 2013;9(7):414-24. [PubMed]
    • Xu L, Freeman G, Cowling BJ et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013;11():108. [PubMed]
    • Hämäläinen P, Vehkavaara S, Perheentupa A. Terveen miehen anabolisten steroidien käyttö. [Anabolic steroid use and anabolic steroid induced hypogonadism]. Finnish Medical Journal Duodecim 2020;136:5-13. In Finnish, abstract in English http://www.duodecimlehti.fi/duo15285.
    • Corona G, Goulis DG, Huhtaniemi I et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology 2020;8(5):970-987. [PubMed]
    • Ng Tang Fui M, Hoermann R, Bracken K et al. Effect of Testosterone Treatment on Bone Microarchitecture and Bone Mineral Density in Men: A 2-Year RCT. J Clin Endocrinol Metab 2021;106(8):e3143-e3158. [PubMed]

Related Keywords ⬆

ATC Code:

G03BA03

Primary/Secondary Keywords