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Measuring testosterone

Chemical pathologist Dr Jaimini Cegla uses a primary care case history to discuss the benefits and pitfalls of testosterone testing

Chemical pathologist Dr Jaimini Cegla uses a primary care case history to discuss the benefits and pitfalls of testosterone testing

The case

A 48-year-old male attends clutching a printout of investigations from a private health screening company. All his tests are normal apart from a testosterone level of 10nmol/l, which is described as low.

On further questioning, he says he arranged the medical because he had been feeling ‘out of sorts' for some time. He works in a high-powered job in the city and his marriage is on the rocks. As a result, his alcohol intake has increased to about 35 units a week, and he's been feeling quite depressed. His sex drive is reasonable but he has been troubled with some erectile dysfunction over the past year or so.

He has no other clinical history and is on no medication. Since his private medical, he's become convinced that he's going through the male menopause and that testosterone replacement is the answer.

How should testosterone levels be interpreted?

Plasma testosterone levels should not be interpreted in isolation. When you request a testosterone level, this result reflects total plasma testosterone. In the circulation, 97% of testosterone is bound to protein: to albumin (loosely bound) and sex hormone-binding globulin (SHBG) (tightly bound).

Importantly, it is the free testosterone that has biological activity. So the free testosterone level depends on SHBG and albumin concentrations, as well as total testosterone levels. There are many factors that affect SHBG concentration (see below).

The free androgen index (FAI), which is a ratio of testosterone-SHBG concentration, can be used to give us an idea of free testosterone levels. This is particularly helpful if the total testosterone result is towards the lower end of the range.

The FAI was first developed to investigate hirsute women with polycystic ovary syndrome. It is less reliable in men because they have lower SHBG levels.

Recently, the Vermeulen equation has been developed and is used by some laboratories. This takes into consideration SHBG and albumin to give an estimate of free testosterone levels. Borderline total testosterone or FAI results are probably best discussed with your local laboratory consultant or endocrinologist.

How much variation is there in testosterone levels within and between individuals?

Secretion of gonadotrophins (LH and FSH) is pulsatile, so testosterone secretion levels can vary by up to 30% between individuals. Specialist centres will often take several samples over an hour to account for this.

There is also racial variation in testosterone levels with men of Afro-Caribbean origin having slightly higher testosterone levels than Caucasians.

Do levels vary with age and with circadian rhythm? How does this affect interpretation?

Prepubertal testosterone levels are low. At the age of six to seven, there is increased secretion of adrenal androgens resulting in a slight rise in total plasma testosterone. This is called adrenarche. At puberty, increased LH secretion results in higher plasma levels of testosterone.

By the ages of 16-18, testosterone levels have usually reached the adult range. There is a gradual decrease in free testosterone levels after the age of 40, accompanied by an increase in SHBG. In elderly men, total plasma testosterone is slightly reduced.

Plasma testosterone levels can vary significantly during the day and are generally highest in the morning, so it is best to sample at the same time – around 9am – every morning.

If a testosterone result is viewed as low, should other tests be performed to look for any cause or association? If so, what?

If testosterone is deemed to be truly low, it is important to determine whether this is primary disease (hypergonadotrophic hypogonadism) or secondary disease (hypogonadotrophic hypogonadism).

In the former, feedback to the pituitary would result in a raised LH and FSH, whereas in secondary disease, LH and FSH would be low. So measuring the gonadotrophins is key to the diagnosis.

Specialist endocrine testing for primary hypogonadism would include human chorionic gonadotrophin (hCG) testing to assess Leydig cell function.

Semen analysis is useful to establish whether the seminiferous tubules are functioning. If Klinefelter's syndrome is suspected then karyotyping would be indicated.

In secondary hypogonadism, dynamic function testing would include clomiphene /GnRH stimulation. Full anterior pituitary function testing would also be warranted, looking particularly for panhypopituitarism and hyperprolactinaemia.

What correlation is there between testosterone levels and the symptoms of the so-called ‘male menopause'?

The terms ‘male menopause' and ‘andropause' are inaccurate as androgen secretion in men does not cease like the menstrual cycle in women but declines very gradually with age.

The symptoms of testosterone deficiency are similar to those that occur with age, including fatigue, reduced mood, decreased libido, erectile dysfunction, bone fragility and reduced muscle mass. So it can be challenging to tell whether symptoms are related to age or whether testosterone deficiency may be contributory.

Also, studies have found no correlation between testosterone levels in ageing men and their symptoms, as defined by the Ageing Males' Symptoms (AMS) Scale1.

Erectile dysfunction, in particular, can be due to a number of causes including psychological and pharmacological causes, peripheral vascular disease and autonomic neuropathy.

Nevertheless, several groups have found that testosterone replacement in ageing, hypogonadal men can improve many symptoms that may be attributable to their low testosterone levels.

So a 2005 consensus document recommends testosterone replacement therapy in men who have a combination of symptoms and low testosterone levels2.

The risk versus benefit of therapy must be considered before commencing treatment and the patient must be carefully monitored.

Dr Jaimini Cegla is an SpR in metabolic medicine and chemical pathology at Imperial College NHS Trust. She would like to thank

Dr John Wong, consultant chemical pathologist at Kingston Hospital NHS Trust, for reviewing the article

Competing interests None declared

The Lab Test Update series is edited by Dr Stuart Smellie, who is consultant chemical pathologist for the County Durham and Darlington Acute Hospitals NHS Trust, and associate director of specialist interests at the Association for Clinical Biochemistry

Blood sample from middle-aged man

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