Testosterone deficiency syndrome; testosterone deficiency; primary hypogonadism; secondary hypogonadism; hypergonadotrophic hypogonadism; hypogonadotrophic hypogonadism
Male hypogonadism describes a state of low levels of the male hormone testosterone in men. Testosterone is produced in the testes and it is important for the development of male characteristics such as deepening of the voice, growth of facial and pubic hair, and growth of the penis and testes during puberty. In the hypothalamus, kisspeptin causes the release of Gonadotrophin-releasing hormone, which in turn stimulates the pituitary gland to produce luteinising hormone and follicle stimulating hormone (gonadotrophins). The gonadotrophins then act on the testes causing them to produce testosterone. Low levels of testosterone can occur due to disease of the testes or from conditions affecting the hypothalamus or pituitary gland. Men can be affected at any age and present with different symptoms depending on the timing of the disease in relation to the start of puberty. In some cases, it can be difficult to tell if there is a true deficiency of testosterone, particularly when the levels are in the borderline range.
Male hypogonadism can be divided into two groups. Classical hypogonadism is where the low levels of testosterone are caused by an underlying specific medical condition, for example Klinefelter's syndrome, Kallmann’s syndrome or a pituitary tumour. Late-onset hypogonadism is where the decline in testosterone levels is linked to general ageing and/or age-related diseases. Additionally, obesity and type 2 diabetes can be associated with hypogonadism in men.
There are two types of classical male hypogonadism – primary and secondary. Primary hypogonadism occurs when the low level of testosterone is due to conditions affecting the testes. Primary hypogonadism is also referred to as hypergonadotrophic hypogonadism, whereby the pituitary produces too much luteinising hormone (LH) and follicle stimulating hormone (FSH) (gonadotrophins) to try and stimulate the testes to produce more testosterone. However, as the testes are impaired or missing, they are not able to respond to the increased levels of gonadotrophins and little or no testosterone is produced. In some patients with primary hypogonadism, testosterone levels may be within the normal range, but the increased LH and FSH indicate that the pituitary gland is trying to compensate for a deficiency and treatment may still be needed.
Examples of conditions affecting the testes, which lead to primary gonadal failure, include:
Secondary hypogonadism occurs when signalling to the testis is unable to stimulate sufficient testosterone production and is caused by conditions affecting the function of the hypothalamus and/or pituitary gland. It is also known as hypogonadotrophic hypogonadism due to low levels of LH and FSH resulting in decreased testosterone production. Secondary hypogonadism often occurs as part of a wider syndrome of hypopituitarism. Examples of causes can include:
The signs and symptoms depend on the stage at which the patient presents with hypogonadism in relation to sexual maturity. If testosterone deficiency occurs before or during puberty, signs and symptoms are likely to include:
Around the time of puberty, boys with too little testosterone may also have less than normal strength and endurance, and their arms and legs may continue to grow out of proportion with the rest of their body.
In men who have already reached sexual maturity, symptoms are likely to include:
As some of these symptoms (e.g. tiredness, mood changes) can have multiple causes, diagnosis of male hypogonadism may sometimes get missed initially.
Male hypogonadism is more common in ageing men. The levels of testosterone in men start to fall after the age of 40. It has been estimated that 8.4% of men aged 50–79 years have testosterone deficiency. Male hypogonadism is also linked with type 2 diabetes: approximately 17% of men with type 2 diabetes are estimated to have low testosterone levels.
Male hypogonadism does not run in families. There are genetic causes of hypogonadism, which include Klinefelter’s syndrome and Kallmann’s syndrome; however, these conditions occur sporadically, they are not inherited from the parents.
A detailed medical history should be taken. In particular, it is important to find out if virilisation (development of normal male characteristics) was complete at birth, whether the testes descended and to see if the patient went through puberty at the same time as his peers. The patient should be thoroughly examined and the presence and size of the testes recorded, and whether they are correctly positioned in the scrotum.
Many of the symptoms of male hypogonadism are non-specific and can be caused by a range of conditions. Therefore, when diagnosing hypogonadism, it is important that biochemical tests are performed to assess the levels of testosterone in the blood to confirm diagnosis. Blood tests will be carried out to measure testosterone levels. The blood sample should be collected in the morning between 08:00 and 10:00 when testosterone levels are highest (as levels of testosterone change throughout the day) and in the fasting state (because eating can lower testosterone levels). The blood test can be carried out as an outpatient appointment. If the result of the first test shows a low level of testosterone, the test should be repeated after two or three weeks to confirm the result. Other hormones are also tested along with the second blood sample. These hormones include luteinising hormone, follicle stimulating hormone and prolactin (produced by the pituitary gland). The results of these blood tests will help distinguish between primary (low testosterone and high gonadotrophins) and secondary (low testosterone and normal or low gonadotrophins) hypogonadism. Testosterone is carried around the blood stream by a protein called Sex Hormone Binding Globulin (SHBG). SHBG is often checked at the same time as testosterone as it makes it easier to interpret whether there is a true deficiency. In patients with obesity and type 2 diabetes, SHBG is often low which can make the testosterone level appear lower than it really is.
Depending on the findings of the above tests, other investigations may be carried out. These include: a bone density scan to assess the impact of testosterone deficiency on bone; semen analysis; genetic studies; an ultrasound of the testes to check for nodules or growths; and an MRI scan of the pituitary gland.
Treatment of classical hypogonadism involves replacement of testosterone with the aim of raising the level of testosterone in the blood to normal levels. Exact treatment will vary between patients and be tailored to their individual needs. Different preparations of testosterone are available:
All of these options should be discussed with a medical professional and the most appropriate treatment option chosen. During treatment with testosterone replacement, regular blood tests should be carried out to monitor testosterone levels and if necessary, the dose adjusted to ensure levels return to the normal range. Tablet forms of testosterone taken by mouth are not recommended due to a link with liver damage, and because it is more difficult to monitor replacement.
Testosterone should not be given if the patient has prostate cancer, because it might make the tumour grow more quickly. Before starting treatment with testosterone, a blood test to measure a hormone produced by the prostate called PSA (prostate-specific antigen) is carried out (PSA levels are elevated in prostate cancer). The prostate may also be examined (via the back passage) to rule out prostate cancer.
For patients who have been diagnosed with late-onset hypogonadism, there is currently not enough evidence for us to know whether treatment with testosterone is safe and effective over the long term. While there are some short-term studies that indicate it may benefit these patients over a short period of time, there is a need for longer-term clinical trials in this area, following a large number of patients, to assess the long-term impact of testosterone treatment on patients with late-onset hypogonadism. Areas that particularly require focus are assessing the effects of treatment on the likelihood of developing cardiovascular disease, prostate cancer and secondary polycythaemia (a condition in which there are increased numbers of red blood cells in the blood, which may predispose to increased blood clots).
If patients have any concerns about their health, they should contact their GP in the first instance.
There can be mild side-effects of testosterone replacement depending on the form used: injectable forms can cause pain and bruising at site of injection; the gel form can cause skin irritation.
Treatment with testosterone can cause an increase in red blood cells (known as polycythaemia), which increases the risk of thrombosis. Regular blood tests should be carried out during treatment to check for an increase in red blood cells. Enlargement of the prostate is another serious side-effect that should be monitored. Prostate examination and a blood test for PSA should be performed every three months for the first year and then annually in men over the age of 40 years after starting treatment. If patients have any concerns about these possible side-effects, they should discuss them with their doctor.
Symptoms of male hypogonadism, such as lack of sex drive, inadequate erections (erectile dysfunction) and infertility, can lead to low self-esteem and cause depression. Professional counselling is available to help deal with these side-effects; patients should talk to their doctor for more information. Patients generally see an improvement in their sex drive and self-esteem following testosterone replacement therapy. Erectile dysfunction is a common symptom in patients without hypogonadism and may need treatment in addition to testosterone.
Male hypogonadism has been linked with an increased risk of developing heart disease (low testosterone can cause an increase in cholesterol levels). Studies have shown that testosterone levels can be lower in men with type 2 diabetes and in men with excess body weight. However, it is not clear whether this is an association or a direct cause and effect. Lifestyle changes to reduce weight and increase exercise can raise testosterone levels in men with diabetes.
Testosterone levels in men decline naturally as they age. In the media, this is sometimes referred to as the male menopause (andropause) although this is not a generally accepted medical term. Low testosterone levels can also cause difficulty with concentration, memory loss and sleep difficulties. Current research suggests that this effect occurs in only a small group of ageing men. However, there is a lot of research in progress to find out more about the effects of testosterone in older men and also whether the use of testosterone replacement therapy would have any benefits.
Last reviewed: Nov 2021