Sponsored by an educational grant from Solvay
Thank you, Mr. Chairman, ladies and gentlemen. First of all, I would like to thank the organizers for inviting me to this interesting symposium and in my first presentation, I will cover the question, how to select the right patient for testosterone replacement therapy?
If we ask this question, we should look what are the current indications for testosterone administration in males. They are listed here: it is male hypogonadism, it is constitutional delay of puberty, treatment of over-tall stature, treatment of aplastic renal anaemia, in young boys with androgen insensitivity, treatment of micropenis, microphallus, and probably in the future there will be a (inaudible) use of testosterone for male contraception. But as you see on that slide, now the most prevalent indication is testosterone replacement therapy of male hypogonadism. So this is the main indication and therefore I would like to shortly review the pathology of male hypogonadism: primary, secondary and late onset hypogonadism.
Here you can see a diagram on the endocrine regulation of testicular function. Testosterone is produced in the Leydig cells of the testis and the Leydig cells are assimilated from the LH from the pituitary gland and LH secretion is stimulated by GnRH from the hypothalamus.
Now in primary hypogonadism, for example in Klinefelter’s Syndrome, the problem is on the level of the testis and there is low testosterone, meaning endocrine hypogonadism, and because there is no negative feedback, there is increased gonadotrophins. So in primary hypogonadism, you have low testosterone and high gonadotrophins.
In secondary hypogonadism, the problem is at the level of the hypothalamus of the pituitary and this can be, for example, prolactinoma or Kallmann Syndrome. In this case, the gonadotrophins are low, LH is low and testosterone is low. Low gonadotrophins, low testosterone, is secondary hypogonadism. This is important for treatment. For example, if paternity is desired, you give different treatments, to assimilate gonadotrophins, but if no paternity is desired, first you should treat the disease, such as prolactinoma and in most cases for example Kallmann Syndrome, if no paternity is desired, you will also give testosterone therapy. Now in late onset hypogonadism, we have a mixed situation and it is known that in late onset hypogonadism of older men, there are problems at all three levels: testicular, pituitary and hypothalamic level.
Now it is well know that there is a decrease, an age-related change of testosterone in healthy men. There are many studies – I am only showing one from Eckhard Leifke – in 572 healthy, non-obese men and as you can see there is a decrease of total testosterone with increasing age and even steeper decrease of the bio-available testosterone. But it is very clear from this diagram that there is a significant scattering of the individual values and this now is a question: how can we select the individual patients who will benefit from testosterone replacement therapy and who will not have side-effects of the therapy, because this might be a difficult task in late onset hypogonadism.
There are recommendations recently published on the investigation, this is the selection of the patient, the treatment and the monitoring and these recommendations came from the International Society of Andrology, International Society for the Study of the Aging Male and European Academy Association of Urology. I should mention that there were initial recommendations of the ISSAM and one of our chairs, Dr. Morales, together with Dr. Lunenfeld, published these recommendations in 2002. But at the last Aging Male Congress in Prague, there was a panel discussion which involved all interested in this field and later, the International Society of Andrology sent a draft of these recommendations to all national societies of andrology for comment and at the time I received these recommendations, there was a consensus from all over the world were published last year and can be used for the correct selection and best treatment of patients with hypogonadism.
I just would like to mention the first statement which is quite important. There is a very clear definition of late onset hypogonadism: it is a clinical and biochemical syndrome associated with advancing age and characterised, and this is important, by typical symptoms and a deficiency in serum testosterone levels. So this for the first time a very clear definition on LOH. So LOH is really a clinical syndrome and so we should shortly talk about the clinical symptoms and they are listed in these recommendations, for example, diminished sexual desire, libido and erectile quality, and this will be covered in the next talk, but there are also changes in mood, a concomitant decrease in intellectual activity, cognitive function, spatial orientation ability, fatigue, depressed mood and irritability, sleep disturbances, decrease in lean body mass and decrease in muscle volume and strength, increase in visceral fat, decrease in body hair and skin alterations and last, a decreased bone mineral density resulting in osteopenia, osteoporosis and increased risk of bone fractures. Because of time, I only would like shortly to talk about the last clinical symptom, about bone mineral density and it is very known today that bone mineral density depends on the androgen level.
This is one study from Michael Zitzmann from Eberhardt Nieschlag’s lab who measured bone density by quantitative ultrasonography and here is a three-dimensional diagram showing bone density on this axis and this was measured in 224 eugonadal men and 156 untreated hypogonadal men. Now if you look at this axis here, here are the testosterone levels and here are the ages, the age from 20 to over 60. And now if you look from the left to the right, you can see this well-known decrease of bone mineral density with advancing age, but you also can see that this decreasing testosterone levels from the back to the front, there is a bigger decrease of bone mineral density in each of the age groups, so this is true for the young hypogonadal men, but also for older men with LOH and this is now common knowledge. But the big question which was discussed quite often at the recent conferences was does this have any clinical relevance because this is only bone mineral density, does this result in bone fractures?
There is a recent quite good study that was published in the New England Journal of Medicine which really proves that androgen deficiency will result in increased fracture rates. This is a study in more than 50,000 men older than 65 with a diagnosis of prostate cancer and the group of investigators looked at two groups: one group of these patients that was not treated with androgen deprivation and a second group of patients who received androgen deprivation. The primary outcome of this study was occurrence of a fracture, so it is not bone mineral density, occurrence of a fracture and occurrence of a fracture resulting in hospitalisation. For all other known factors, there was adjustment and the result of this study is very important: of those men surviving at least five years after diagnosis, 19.4% of those who had received androgen deprivation therapy had fracture as compared to 12.6% of those not receiving androgen deprivation. So this really shows that androgen deprivation will result in an increased bone fracture rate. In addition to this general result, these authors could show that especially the fractures resulting in hospitalization will be increased and they also showed which is important, that the risk was higher when the patients received longer androgen deprivation therapy, so there is clearly a dose effect.
Now these were clinical symptoms. Now I would like to come to the biochemistry. If you want to confirm hypogonadism, we measure testosterone in serum as we cannot measure the tissue levels, but there are certain aspects that have to be considered when interpreting these results. The first one is clearly a pre-analytic aspect.
It is well-known and it was again shown by this very nice study by Michael Diver that there is a significant circadian variation or circadian rhythm of testosterone and this is true for young men, as shown here, and elderly men. Here you can see the time in clock hours and you see the maximum level of testosterone as seen in the morning. If you take a blood sample in the late evening, in normal physiology this will be on average more than 40% lower. So it is quite important if you take blood samples in the morning, then you should use reference range for the morning levels and actually the recommendations say that the blood should be taken between 7:00 am and 11:00 am.
Another aspect which is important for the interpretation of the testosterone level is shown here and this, as you know, testosterone is bound to proteins in serum. It is specifically and strongly bound to SHBG, 50% to 60%, it is loosely bound to albumin, 40% to 50%, and free testosterone is about 1% to 2%, and this is loosely bound, we consider the albumin bound and free testosterone as a bioactive testosterone because this can enter the surge and excavate the androgen receptor. In normal clinical settings, it is sufficient to measure total testosterone, but if there is a change in the SHBG, there is a good reason to also measure the free or bio-available testosterone. There are many instances, many cases with SHBG is influenced. I just would like to say age, this is important for late onset hypogonadism, with an increase in SHBG but also obesity and men with high BMI on average; they might have quite low SHBG levels. What does this mean? This patient might have low total testosterone, but as the SHBG is also low, the bio-available testosterone is at the normal range and this patient is not hypogonadal.
So in summary, what I have said, how to select the right patient. We say prior to the initiation of testosterone therapy, there should be a clear indication based on the clinical picture, together with biochemical evidence of low testosterone and, and I would like to stress this, there are contraindications for replacement therapy have to be excluded and I shortly would like to show the major contraindications, the absolute contraindications here in bold are suspected or proven carcinoma of the prostate or, carcinoma of the breast, but also significant polycythemia, untreated sleep apnea, severe heart failure, severe symptoms of lower urinary tract obstruction, due to ab enlarged, clinically benign prostate and a partial contraindication might be a moderate obstruction.
In my last slide, I would like to show you an algorithm which might help really to select the right patient, to select the patient who will benefit from treatment and in whom we can avoid side effects. This is based on these recommendations. So we start with the clinical symptoms of late onset hypogonadism; again, it is a clinical syndrome, the patient comes with clinical symptoms and there should be a clear and physical work-up, but also then biochemical measurement of total testosterone and SHBG in the morning as I said before, and then it depends on the level of testosterone. So you can see here a normal level, higher than 12, an intermediate range, 8 to 12 nmol/L, and a sub-normal range, lower than 8 nmo/L. Now it is agreement that a man with normal testosterone, there is no reason for replacement, so there is no androgen deficiency and other reasons for the clinical symptoms have to be considered.
In the intermediate range between 8 and 12 nmo/L for total testosterone, the free testosterone should be calculated by a total T and SHBG and if this is normal, there should be no androgen therapy.
If this is sub-normal, the free testosterone its the same when the total testosterone is sub-normal, there should be a repeat measurement of testosterone and the gonadotrophins, prolactin, and the low testosterone has to be validated or the low free testosterone, and then it depends whether the gonadotrophins are high, normal or increased with the primary hypogonadism or whether the gonadotrophins are low, or low-normal or prolactin is significantly elevated, the secondary hypogonadism, the primary contraindications have to be excluded, then you can start testosterone substitution and it is quite important to do close monitoring by PSA and hematocrit measurement and validation of clinical improvement. In the case with low gonadotropins, really the pituitary and hypothalamic functions should be evaluated, for example to find a prolactinoma is a reason for the hypogonadism and then there should be proper treatment for example of the prolactinoma and in other cases your patients will also get testosterone substitution.
I would like to close with that algorithm and hope that this will help you to select the right patients for testosterone therapy.
Thank you very much.
Case #1 So this is a patient, a 61-year-old man who actually came to my outpatient department because he had difficulties at work due to competition with a young colleague and actually he wanted to have a check-up, he wanted to have information about his testosterone levels. On clinical examination, this patient had normal male hair pattern, a testicular volume of 18 on the right side, 12 on the left side ml, normal consistency, he had a left-sided third degree varicocele and quite important, the weight of this patient was 150 kg, the height 1.76 m and the BMI was 37.1, so this patient was really obese.
Now we come to the laboratory values in this patient. The LH was normal, 4.2 u/L, and here is the normal range given in brackets. The FSH was elevated, 13.1, normal range 1 to 7 in our laboratory, testosterone is 9.7 nom/L, normal range in our laboratory 12 to 35, and this is about 280 ng/dL, prolactin was normal and hemoglobin was normal and the PSA was high but still in the normal range.
Now comes the question: Would you start testosterone replacement therapy right away in this patient? Would you do additional pituitary function tests? Would you in this patient measure testosterone and SHBG and calculate free testosterone or would you not do any further tests?
I think that is quite interesting. I think the correct best way would be to measure testosterone SHBG and calculate the free testosterone. This patient is really obese and I said before, he might have a low SHBG.
And now we have the additional tests, please go on. The additional tests showed a low SHBG which was still in the normal range, 12.1, the normal range is 11 to 71, and the free testosterone is 297 pmo/L which is clearly in the normal range, that is higher than 250.
Case #2 Now again, one question with two answers on this patient. So when you have the free testosterone which is normal, would you start testosterone therapy or would you not start testosterone therapy but do further investigation for other causes and maybe put this patient on a diet?
So it is very clear and I think this is the correct way and this is actually what was recommended in the recommendations I have shown you before and I would like to thank you, thank you very much.
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