Diagnosis and Treatment of Late-Onset Hypogonadism in Men

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Introduction

An increasingly common problem encountered by clinicians is late-onset hypogonadism (LOH) in men, also referred to as age-associated testosterone deficiency syndrome (TDS). This is a clinical and biochemical syndrome associated with advancing age; it is characterised by a deficiency in serum testosterone levels.^1,2

Testosterone is essential to man’s health and well-being. It has many physiological actions in muscles, bones, hematopoietic system, brain, reproductive and sexual organs, and adipose tissue. LOH may greatly reduce quality of life and adversely affect the function of multiple organ systems.³

The symptom most associated with LOH is reduced libido. Other symptoms include fatigue, decreased muscle mass and strength, decreased motivation, cognitive impairment, decreased self-confidence, depression, osteoporotic pain, and erectile dysfunction.^1,3

In primary hypogonadism the luteinising hormone (LH) and follicle stimulating hormone (FSH) levels are usually elevated, meaning the problem originates in the testes, whereas in secondary hypogonadism, both LH and FSH are normal or low, suggesting the problem lies above the level of the testes and is due to issues with the pituitary or hypothalamus. LOH is defined as hypogonadism in a male who has had normal pubertal development and as a result developed normal male secondary sex characteristics. LOH is often secondary hypogonadism in nature.⁴

The Endocrine Society recommends testosterone therapy for men with confirmed LOH to maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density.⁴

Risk factors for LOH in older men include chronic illnesses (including diabetes mellitus, chronic obstructive lung disease, inflammatory arthritic, renal and HIV-related diseases), obesity, prolactinoma, excessive alcohol consumption, metabolic syndrome, haemachromatosis, chronic opiate therapy, and androgen deprivation therapy (for prostate cancer). Such chronic conditions should be investigated and treated.¹

Testosterone therapy in men with low testosterone levels may improve metabolic status by lowering blood sugar and HbA1C in men with type 2 diabetes, reducing abdominal girth, improving features of the metabolic syndrome, all of which may be protective of the cardiovascular system.⁵

Diagnosis

Clinical symptoms

The diagnosis of LOH requires the presence of symptoms suggestive of testosterone deficiency, as well as biochemical evidence, i.e. appropriate symptoms AND ≥ 2 measurements of low testosterone.

Symptoms associated with hypogonadism include:

• reduced libido
• decreased vitality and depressed mood
• decreased muscle mass and strength
• increased body fat
• erectile dysfunction
• absence of morning erections
• delayed ejaculation
• decreased bone mineral density

None of these symptoms are specific to the low-androgen state, but may raise suspicion of testosterone deficiency.^1,2,4,6

Laboratory testing

The most widely accepted parameter to establish the presence of LOH is the measurement of serum total testosterone.

For serum total testosterone determination blood should preferably be taken at 9am and certainly between the hours of 7am and 11am, without fasting.

• There is general agreement that total testosterone level ≥ 12 nmol/L does not require substitution.

• There is also consensus that patients with total testosterone levels ≤ 8 nmol/L will usually benefit from testosterone replacement therapy.

• If total testosterone level is 8 to 12 nmol/L, repeating the measurement of total testosterone with sex hormone-binding globulin to calculate free testosterone may be considered. In the presence of clinical symptoms suggesting testosterone deficiency and borderline serum testosterone levels, a short therapeutic trial may be justified. Testosterone administration should be discontinued if no response is observed.

• Measurements of serum levels of LH and FSH will assist in differentiating between primary and secondary hypogonadism, and a determination of serum prolactin level is indicated when the serum testosterone is lower than 5.2 nmol/L or when secondary hypogonadism is suspected. The prolactin level should be measured to avoid missing a prolactinoma.

Due to variability in laboratory values, all measures of testosterone should be carried out in the same laboratory. Methods based on mass spectrometry are more accurate and precise and are increasingly recognised as the method of choice for serum testosterone measurement.

Other etiology (which may be responsible for the clinical symptoms) should be excluded before therapy is started.

Transient decreases of serum testosterone levels, such as due to acute illnesses, should be excluded by careful clinical evaluations and repeated hormone measurement.^1,6

Pre-Treatment

Prior to therapy with testosterone, a man’s risk of prostate cancer must be assessed using digital rectal examination and determination of serum prostate-specific antigen (PSA).

The pre-treatment assessment can be improved by incorporating other risk predictors such as age, family history, and ethnicity/race. The use of testosterone therapy in men with locally advanced or metastatic prostate cancer is contraindicated.

Men successfully treated for prostate cancer and suffering from confirmed LOH are potential candidates for testosterone substitution after a prudent interval (≥ 2 years) if there is no clinical or laboratory evidence of residual cancer.

Older men should be counselled on the potential risks and benefits of testosterone replacement before treatment and carefully monitored for prostate safety during treatment.

Severe symptoms of lower urinary tract symptoms evident by a high International Prostate Symptom Score due to benign prostate hyperplasia represent a relative contraindication. After successful treatment of lower urinary tract obstruction, this contraindication is no longer applicable.

Men should not be started on treatment with testosterone without prior resolution of the following conditions:

• Prostate or breast cancer
• Severe lower urinary tract symptoms
• Significant erythrocytosis (haematocrit >50%)
• Untreated obstructive sleep apnoea
• Untreated heart failure

Individual assessment of co-morbidities (as possible causes of symptoms) and of the potential risks versus benefits of testosterone treatment is of increasing importance with greater age.^1,2,6

Testosterone Treatment

Preparations of natural testosterone should be used for substitution therapy. Intramuscular, transdermal, and oral preparations of testosterone currently available in Ireland are listed in Table 1. Choice of preparation should be discussed with the patient.

Since the possible development of an adverse event during treatment (especially elevated haematocrit or prostate carcinoma) requires rapid discontinuation of testosterone substitution, short-acting preparations may be preferred over long-acting depot preparations in the initial treatment of patients with LOH.¹

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Monitoring

Testosterone level should be monitored at baseline and at regular intervals during treatment. The aim of therapy should be a total testosterone level of at least 15 nmol/L to ensure symptomatic improvement. Sustained supra-physiologic levels should be avoided.

Patients should be monitored for prostate safety during treatment, at 3–6 months, 12 months, and at least annually thereafter. The combined application of digital rectal examination and PSA and improves the prostate cancer detection rate over either test alone.

Erythrocytosis can develop during testosterone treatment. Haematological assessment is indicated before treatment, then at 3 months and 12 months, and annually thereafter. The haematocrit value should be kept below 52-55%.

Improvement in symptoms of LOH should be sought. Failure to benefit clinical manifestations within a reasonable time interval (6 months is adequate for libido and sexual function, muscle function, and improved body fat; improvement in bone mineral density requires a longer interval to show improvement) should result in discontinuation of treatment. Further investigation for other causes of symptoms should then be considered.^1,6

References:

1. Wang C. et al. Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Males: ISA, ISSAM, EAU, EAA, and ASA Recommendations. Eur J Endocrinol 2008; 159(5): 507–514.
2. Wylie K. et al. Androgens, health and sexuality in women and men. Maturitas 2010; 67: 275-289.
3. Bain J. Testosterone and the aging male: To treat or not to treat? Maturitas 2010; 66: 16-22.
4. Bhasin S. et al. Testosterone therapy in adult men with androgen deficiency syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010; 95(6): 2536–2559.
5. Heufelder AE. et al. Fifty two week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycaemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Andrology 2009; 30(6): 726-733.
6. Wylie et al. Guidelines on the management of sexual problems in men: the role of androgens. British Society of Sexual Medicine. 2010. Available at: http://www.bssm.org.uk/downloads/UK_Guidelines_Androgens_Male_2010.pdf

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Caroline McDermott