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Testosterone deficiency—the male menopause?
Executive Editor, InnovAiT
E-mail: chantal.simon{at}oxfordjournals.org
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Abstract |
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 TOP Abstract The GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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Testosterone deficiency in older men as a result of testicular failure is commonly termed the ‘andropause’ or ‘male menopause’. This is a misleading term as it implies a sudden and complete cessation of male sex hormone production and resulting loss of fertility. In reality, the process is more of a gradual decline with reduction, and not cessation, of testosterone production. As a result, other terms have also been used to describe the same phenomenon. These include ‘symptomatic late onset hypogonadism’, ‘androgen deficiency (or decline) of the ageing male’, or ‘partial androgen deficiency in ageing males’.
Roughly, 2 million adult men in the UK are thought to have testosterone deficiency. Studies of ageing men typically show that around 2–3% of men aged 20–29 have testosterone deficiency. This figure rises to 10% in those aged 40–49 years and to 30% in the 60- to 69-year-old age group. However, studies also show that up to 25% of men have no decline in testosterone levels with age and there are many examples of men fathering children into old age. This raises the question of whether testosterone deficiency is a natural part of the ageing process that all men go through or due to a disorder (or disorders) that result in reduction in testosterone production.
Statement 10.2 of the GP curriculum (Men's health) lists the andropause as a common and important condition within the knowledge base for that topic.
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Presentation of hypogonadism |
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TOPAbstractThe GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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One of the major problems with detection of testosterone deficiency is that symptoms and signs are non-specific, inconsistent and often put down simply to the ageing process. Typical symptoms and signs include:
- Slowed growth of secondary body hair in the axillae, genital and beard area. Male pattern baldness is not associated with testosterone deficiency.
- Progressive decrease in muscle mass
- Increased upper body and central body fat
- Loss of libido
- Erectile dysfunction
- Oligospermia or azoospermia
- Lethargy and/or poor ability to concentrate
- Mood changes including depression, anxiety, anger and aggression
The voice and the size of the penis usually remain unchanged. In patients with gradual, age-related hypogonadism, hot flushes are rare.
| Case history 1 Mr S is a 62-year-old man who has always been fit and healthy. He comes to the surgery to see you because he is generally out of sorts. He is lethargic and has lost his ‘get up and go’ and has noticed mood swings. He mentions that he is not getting on very well with his wife. On further questioning, he tells you that he seems to have lost his sex drive and is having problems with erectile dysfunction.
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Types of hypogonadism |
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TOPAbstractThe GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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Testosterone deficiency or male hypogonadism has two major forms—primary (hypergonadotrophic) hypogonadism and secondary (hypogonadotrophic) hypogonadism. In men, primary hypogonadism is associated with testicular failure. There are many possible causes of testicular failure. These include:
- Chromosome abnormalities—Klinefelter's syndrome often goes undiagnosed until detected in the course of infertility investigations
- Testicular dysgenesis syndrome
- Undescended testicles at birth
- Tumours—testicular cancer, childhood leukaemia and treatment for other cancers with chemotherapy or radiotherapy
- Infection—particularly mumps and HIV infection
- Haemochromatosis
- Injury to the testicles—acute trauma, torsion, burns or repeated low-level injury such as that seen in cyclists
- Drugs, for example chemotherapy agents, glucocorticoids, opioids, ketoconazole, frequent heavy use of marijuana
The other major type of hypogonadism is secondary hypogonadism. In secondary hypogonadism, the gonad stimulating pituitary hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH), are absent or produced in insufficient quantities (Fig. 1). This results from disease of the pituitary gland or hypothalamus. LH and FSH stimulate the testes to produce testosterone and their deficiency results in decreased testosterone production from normal testes. The most common causes of secondary hypogonadism in adult males are as follows:
- Pituitary tumours or treatment for brain tumours elsewhere—10% of intracranial tumours are pituitary tumours. They present with local pressure effects (bilateral hemianopia, cranial nerve palsies and/or headache) and/or hormone effects.
- Serious systemic illnesses, including HIV infection and tuberculosis
- Malnutrition or obesity
- Medications such as opioids, steroids or gonadotrophin releasing hormone (GnRH) analogues
- Hyperprolactinaemia
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Patients with hypothalamic disease have a reduction in GnRH. GnRH is released by the hypothalamus to stimulate LH and FSH production. These patients will have low testosterone levels in association with low or normal LH and FSH levels.
| Case history 2 On examination of Mr S, you notice that he is a little obese and his axillary hair growth is sparse. Otherwise, there are no abnormal findings. Although cardiovascular disease and diabetes are the most common causes of erectile dysfunction in men, Mr S's loss of libido makes you suspect possible testosterone deficiency. As well as checking a depression score, you decide to do a routine blood screen including full blood count, renal and liver function, fasting glucose, thyroid function tests and serum testosterone levels. The results come back normal apart from a serum testosterone just below the lower limit of normal.
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Testing for hypogonadism |
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TOPAbstractThe GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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Measurement of testosterone and sex hormone-binding globulin levels
Another problem with diagnosis of hypogonadism in ageing men is measurement of testosterone levels. Men with no symptoms may have low total levels of testosterone whereas only 13% of those complaining of symptoms or signs suggestive of testosterone deficiency have total testosterone levels below the normal range.
There are several reasons for these findings. Firstly, testosterone levels vary from hour to hour. For example, testosterone levels may be low the morning after a man has consumed a large amount of alcohol or raised if the patient is fasting. There is also a diurnal rhythm of testosterone production so that the highest levels of circulating testosterone are seen in the early morning. Therefore, testosterone levels should be measured in the morning, and measurement should be repeated in patients with subnormal levels of testosterone, especially in those with no definite signs or symptoms of hypogonadism.
Secondly, testosterone circulates largely in bound form, attached to sex hormone-binding globulin (SHBG) and albumin. The testosterone bound to albumin is only weakly bound and can dissociate easily to become free active testosterone that is ‘bio-available’ for use by the body. Testosterone bound to SHBG is tightly bound and not usable by the body. In young adult men, 2% of circulating testosterone is in the ‘free’ form; 30% is bound to SHBG and 68% is bound to albumin. SHBG levels increase by around 1% per year as men age. Therefore, if a young man and an elderly man have the same total testosterone level, the young man has a higher proportion of usable testosterone than the older man (Fig. 2). Apart from ageing, other factors that increase SHBG levels are hyperthyroidism, liver disease, severe androgen deficiency or oestrogen excess. A low SHBG level may be associated with hypothyroidism, obesity or acromegaly.
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To get around this problem, many laboratories calculate the free androgen index. This is an estimation of the proportion of bioavailable testosterone gained by dividing the total testosterone concentration by the SHBG concentration. However, many endocrinologists feel that this calculation is flawed because if both testosterone levels and SHBG levels are low, a normal result will be obtained when the patient has testosterone deficiency.
An alternative way of measuring testosterone is to directly measure the free testosterone levels. However, several methods of doing this are available and, because albumin binds testosterone weakly, the amount of free testosterone varies with the technique used. Guidance from the United States recommends that the most reliable method of measuring free testosterone is by equilibrium dialysis. Using this method of analysis, around 75% of men with symptoms have low testosterone levels.
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Other tests |
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TOPAbstractThe GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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If serum testosterone levels are low, further tests are required to determine whether any hypogonadism is related to a primary testicular disorder or pituitary/hypothalamic disease. American guidelines recommend checking LH, FSH and prolactin (Table 1). If the testes are not producing enough testosterone, then there is reduced negative feedback from testosterone on the pituitary gland, resulting in increased levels of LH and FSH (Fig. 1). Hyperprolactinaemia is the most common pituitary disorder. It is usually due to a prolactin-secreting pituitary adenoma (prolactinoma).
| Case history 3 You decide to repeat Mr S's testosterone level a week later when he has not been fasting. You add a serum FSH, LH and prolactin to the list of tests ordered. The result comes back and the serum testosterone is well below the lower limit of normal now. Serum LH and FSH are slightly raised and prolactin is normal. This implies that Mr S has primary hypogonadism.
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Complications of primary hypogonadism in older men |
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TOPAbstractThe GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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Many associations have been proposed between low levels of testicular testosterone production and other health effects. The link between low testosterone and osteoporosis is well accepted. In one study of elderly male nursing home residents, the incidence of hip fracture was 5–15%. Of those residents who had sustained a prior hip fracture, 66% were found to have hypogonadism (defined as a serum testosterone levels less than 300 ng/dl), even though many of these men did not have other clinical features of hypogonadism.
There is also an observed association between hypogonadism and the development of metabolic syndrome and type 2 diabetes. Replacement of testosterone in patients with type 2 diabetes and hypogonadism may improve diabetic control and reduce risk of heart disease.
Other studies have shown a link between low testosterone levels and increased cardiovascular and all-cause mortality. A recent study showed that low free testosterone levels resulted in a 3-fold increased risk of premature coronary artery disease in younger men, suggesting that it might be beneficial to screen for low testosterone levels in order to prevent cardiovascular disease. However, currently there is no evidence that identification and treatment of low testosterone levels in this group reduces their risk.
Testosterone also has effects on the central nervous system. Primary hypogonadism has been observed in association with both mild cognitive impairment and Alzheimer's dementia. There is emerging evidence that treatment with testosterone in this group reduces cognitive decline. A low testosterone level is also associated with depression, and older men with depression may benefit from testosterone replacement.
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Treatment of primary hypogonadism in older men |
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TOPAbstractThe GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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If initial investigations suggest secondary hypogonadism, always refer to an endocrinologist for further investigation of the cause. In ageing men, there is some debate over when and how to treat primary hypogonadism and the effects of treatment. As a general principle, treatment should be considered if the potential benefit of treatment exceeds the potential harm. However, the benefits of treatment with testosterone replacement are far from clear.
Choice of preparation
Testosterone is marketed in several different formulations in the UK. Traditionally, men have been treated with testosterone injections, but these must be given weekly and can result in peaks and troughs of testosterone levels. Implants are another option but these require a minor operation to insert them and fine-tuning of the dose is difficult. The effectiveness of oral testosterone, usually in the form of capsules taken four times daily, has been brought into question both because of problems with long-term concordance with taking a four-times-a-day dosage and problems with metabolism of the drug.
The transdermal route is the most effective method of testosterone administration currently available. Daily patches have the draw back of skin irritation and lack of adhesion when men exercise and sweat. The newer gels are the preferred option by most men. They are applied daily and have the advantage that fine-tuning of the dose is relatively easy. Advise men to wash their hands after application. The disadvantages of gel preparations are that they are gooey and men may have worries about transferring testosterone to other close contacts. A testosterone nasal spray is under development. In time, this may takeover from the gel preparations as the treatment of choice.
Before treatment
In the past, there have been worries about testosterone replacement therapy and risk of prostate cancer. The current consensus is that testosterone may exacerbate prostate cancer that is already present, but is not thought to cause the initiation of prostate cancer. Testosterone replacement may even reduce the risk of aggressive prostate cancer.
Before treatment, it is important to perform a prostate symptoms score, check a serum PSA and examine the prostate gland. Patients with an International prostate symptoms score of greater than 19, elevated PSA (more than 3 ng/l) or any suspicion of prostate cancer should be evaluated further by an urologist before treatment with testosterone starts. For patients taking finasteride, consider referring for urology review if the PSA is in the high-normal range.
| Case history 4 After discussion of the pros and cons of treatment, Mr S decides that he would like to try testosterone supplements. You check a serum PSA level and do a prostate symptoms score. You arrange for Mr S to come back after he has had his blood taken for clinical examination of his prostate. The PSA test comes back with a level of 9 ng/l and so you refer Mr S for a urology assessment before starting any treatment.
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Who should be treated?
No specific recommendations have been established. Consider treatment in men with symptoms of hypogonadism and low testosterone levels. Some advocate treatment of all older men with total testosterone levels consistently below 2.0 ng/ml, regardless of whether symptoms are present. Using this guideline, approximately 30% of men over the age of 75 years would require testosterone replacement.
What are the effects of testosterone supplementation?
Testosterone replacement treatment may result in improved lean body mass, increased haematopoiesis, decreased low-density lipoprotein (LDL) levels in conjunction with a constant ratio of LDL to high-density lipoprotein, improved libido and improved well-being in older men. However, symptoms of depression and anxiety respond inconsistently to testosterone replacement. More specific affects on cognitive function in those with impaired cognitive function and insulin sensitivity in those with type 2 diabetes and metabolic syndrome have also been claimed.
| Case history 5 Mr S comes back after seeing the urologist. No evidence of prostate cancer has been found and the urologist has given you the all clear to start testosterone treatment. After discussion with Mr S, he opts to try a testosterone gel. You explain how he should apply the gel and possible side effects.
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Monitoring
Periodic follow-up of patients receiving testosterone therapy is needed. During the first year of therapy, clinical response and side effects should be monitored every 3–4 months. Blood levels of serum testosterone should be measured at each assessment to establish whether testosterone supplementation is sufficient. Aim for a testosterone level in the middle of the normal range:
- For patients receiving testosterone injections, check serum testosterone at the midpoint between injections
- For patients using testosterone patches, peak serum testosterone levels occur 3–12 hours after application
- For patients using testosterone gels, the serum level of testosterone is constant and time of checking is not critical. Measure 1–2 weeks after starting or altering the dose
For men taking long-term testosterone, examination of the prostate should be done routinely, along with a prostate-related symptom score every 6–12 months. PSA levels should be determined annually. Patients with high PSA levels should be referred for further investigation. For patients with osteoporosis and hypogonadism, consider rechecking bone density every 2–5 years.
| Case history 6 Three months after starting the testosterone gel, Mr S comes back to see you. He feels generally much better. His libido has returned although he still has inconsistent erections. His testosterone levels are now in the middle of the normal range and his PSA is unaltered.
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Key points
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References |
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TOPAbstractThe GP curriculum and...Presentation of hypogonadismTypes of hypogonadismTesting for hypogonadismOther testsComplications of primary...Treatment of primary...References |
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