This will be a review of androgen deficiency diagnosis and focus on replacement therapy in men with hypogonadism.
First of all I want to focus your attention on the causes of androgen deficiency.
A very short outline in which I show you that there are different types of hypogonadism, the primary causes, secondary causes, the target organ resistance, and last, but not least, the age related hypogonadism. Between primary hypogonadism I want to remind you that Klinefelter’s Syndrome represents more than 30% of primary hypogonadism in the adult male and between hypothalamic causes, idiopathic hypogonadotropic hypogonadism, and the Kallmann syndrome represents the most important causes.
Let’s move to the patients with hypogonadism. Patients with hypogonadism usually search for medical advice because of infertility. That is the primary referral to the specialist. Then erectile dysfunction, lack of libido, reduced level of energy and vitality, and delayed onset, or development of puberty.
The diagnostic steps comprise and anamnesis and physical examination that are very important to establish the features of hypogonadism. So testosterone, LH and FSH evaluation and other hormonal parameters such as oestrodial that is very important in terms of the balance between testosterone and oestrodial levels, in consideration of the fact that many, many hypogonadal patients are obese. Clinical and chemical parameters, ejaculate analysis, and further specialistic in examinations, such as sonography or more specialised investigations.
The medical history must investigate patients’ complaints, their family and sexual history, the presence or absence of early morning erections, the presence of illnesses that are associated with hypogonadism. So co-morbidities and drug consumption.
What about physical examination? First of all we have to include the blood pressure measurement, then waist:hip ratio measurements. We have to investigate virilisation, pubic hair density and distribution, the penis size, the scrotum and especially the presence of small volume testes, and varicoceles and the prostate examination by digital rectal examination.
What about hormonal diagnosis of hypogonadism? As Dr. Corona outlined before this, there are many, many cut-offs. There have been suggested by many researchers all over the world, first of all we have to examine the testosterone levels and then, afterwards, the LH and FSH rates that are indicators for pituitary function.
What about the cut-offs? These are suggested cut-offs in the literature, you will find a lot of cut-offs varying lab by lab.
The ISSAM recommendation number three, suggests to us that blood samples for testosterone determination less than 8 nmol/L between 7:00 and11:00 a.m. repeated one week apart confirms the diagnosis of overt hypogonadism. You can even use the free-testosterone level, but only when you use the equilibrium dialysis method. And the cut-off for this is 180 Pmol/L. But the easiest way to determine the free testosterone level is to calculate free testosterone from total testosterone, SHBG and albumen level.
In the presence of all of the above you have also to evaluate LH and prolactin to exclude secondary hypogonadism.
Now, is late-onset hypogonadism true clinical entity?
In this conference many people have referred about the decline of testosterone levels in the aging male. In this lies the risk of significant relationship between advancing age and total testosterone levels and moreover, a more important relationship between advancing age and the free testosterone index, and increase in SHBG bound testosterone, indicating that advancing age is associated with physiologic decline in testosterone levels.
The ISSAM recommendation number two tells us that LOH is a syndrome characterised by primarily by lack of libido, decrease in erectile quality and the frequency, and particularly a decrease in the nocturnal erections. Changes in mood, sleep disturbances, decrease in lean body mass with associated diminution of muscle volume and strength, increase in visceral fat, decrease in body hair and skin alteration, and last but not least, osteoporosis.
What is the main indicator of LOH? The decrease in testosterone levels but more important decrease in free testosterone levels and bioavailable testosterone. Questionnaires are very important but are still under debate because many questionnaires are able to discriminate the presence of hypogonadism but have not the requested sensitivity and specificity.
Which are the clinical features associated with hypogonadism?
Many, many epidemiological studies show association between testosterone levels and features of the metabolic syndrome.
As already shown by Dr. Channer there is a very nice paper by Dr. Muller, which shows that total testosterone levels are inversely related to the presence of one, two or three symptoms of metabolic syndrome. SHBG are also inversely related, but more important oestrodial levels, as you can see here in the right part of the slide, in the bottom right part of the slide, there is a nice correlation between higher oestrodial levels and the features of metabolic syndrome.
So what about androgen deprivation?
This is a paper recently appeared in Cancer, the issue of February 2006, by Basaria and co-workers. They showed that if you make an androgen deprivation, pharmacological androgen deprivation in patients with prostate carcinoma, you can see a worsening of all parameters related to metabolic syndrome. Insulin levels increase, glucose levels increase, HOMA levels increase. HOMA is a direct mathematical calculation of insulin sensitivity as you all know, and leptin levels increase. So, when you make a castration, a pharmacological castration, you increase fat mass and leptin is the result.
What about type II diabetes patients and cardiovascular disease?
I want to focus your attention only on these two papers, which recently appeared. One in the JCEM by Dhindsa and co-workers, in which if they considered a cut-off of total testosterone of 10 nmol/L there are 44 incidences of hypogonadism in type II diabetes patients.
This other paper by Corona shows the same. It shows double incidence of hypogonadism in men with type II diabetes between the fifth and sixth decade of life, and they used the cut-off of 12 nmol/L .
What about obesity?
One of the many papers that has appeared in the literature is from an Italian group and shows that controls have higher levels of testosterone than obese men, thus suggesting that fat cells are per se inducing a reduction of testosterone production.
What about testosterone levels and atherogenic risk?
As outlined by Dr. Channer before there is a very important, remarkable, relationship between low testosterone levels and increase of atherosclerosis. And the Rotterdam studies is a proof of facts study demonstrating that the relative risk of atherosclerosis is higher men with hypogonadism. The higher the degree of hypogonadism the higher is the relative risk to develop atherosclerosis.
This is very clearly demonstrated in this study by Fukui in which there was an inverse relationship between mean intima media thickness, and free testosterone levels, and also plaque score of the carotid arteries.
What about treating this man with testosterone? What happens to their metabolic parameters?
Boyanov’s study has very importantly demonstrated a remarkable reduction in all parameters of the metabolic syndrome by using testosterone undecanoate per (inaudible). And you can see here a weight reduction, a waist:hip circumference reduction, a decrease in the percentage of body fat, both in terms of kilograms and percentage.
An improvement in fasting and postprandial glucose and in glycose (inaudible) levels.
What about erectile dysfunction in those patients?
Seftel demonstrated the prevalence rates of concurrent disease in this very large series of patients is present in almost 52% of patients with hypertension or hyperlipidemia, and 20% of diabetes mellitus. Incidence increases with age.
In previous studies we have demonstrated that androgens, circulating androgens are very important to the erectile process. This is a linear regression carried out on 52 patients without any respective for erectile dysfunction. In this paper we showed that the higher the free testosterone levels the higher is the penile inflow into the arteries, into the cavernous arteries. Thus, suggesting that testosterone is an important vasodilator balance control.
What happens to the subjects if you give them testosterone? These patients were affected by erectile dysfunction and were not responders to sildenafil for a long period. As you can see in the slide they were starting from baseline testosterone levels in the grey zone between 11 and 12 nmol/L. Well, if you increase the testosterone level by giving them patches of testosterone for a short term of one month you can increase peak systolic velocity then, resistive index (inaudible) ultrasound and you can improve their erectile function scoring by the IIEF, thus demonstrating that testosterone has a vasodilator properties.
What about patients with mild hypogonadism? We did the same study in men with hypogonadism with baseline testosterone below 10 nmol/L and further demonstrating and confirming data that testosterone improves peak systolic velocities, while not modifying end diastolic velocities, with the concomitant and parallel improvement in IIEF erectile function score and sexual desires scores.
Are the effects produced by testosterone replacement therapy clinically relevant to older men? We do not know this because there are no large studies.
What we did was a meta-analysis to try to investigate, and to demonstrate, the effects of the testosterone on all parameters evaluated in the studies present in the Medline. So, what happened to the sexual function you can see from this slide, on the left side, if you can see the 7.0 nmol/L as a cut-off, there is a clear benefit on sexual desire and on erections. If you consider the cut-off between 7.0 and 12 nmol/L there is still a very important improvement in both libido and erections. If you consider a cut-off of 12 nmol/L the improvement is still persistent but at less greater extent, thus demonstrating that the higher the baseline testosterone, the less the effect on the libido and on the erection itself.
What about body composition? The same if you consider a cut-off of 10 nmol/L there is a significant decrease in total fat mass, and in fat-free mass, if you consider above 10 nmol/ml. There is a smaller but still significant increase in both total fat mass and fat-free mass.
What about bone? The effects on BMD, on total BMD, were significant but were not pronounced as bone resorption markers and bone formation markers that I am showing in this slide. So you can see here that there is a decrease in bone resorption markers and bone formation markers, thus showing that after prolonged testosterone therapy subjects respond better than placebo treated men.
What about serum lipid profile effects? Total cholesterol has a remarkable reduction paralleled by HDL cholesterol reduction, but as you can see in this slide the reduction in HDL is more pronounced than in total cholesterol thus suggesting a possible protective effect of testosterone on the progression of atherosclerosis. This is a possible effect. It has not been demonstrated in larger studies.
Which are in most need of treatment?
As you can see in this slide, we proposed this model and the model is that the less the testosterone baseline, the best is the effect, especially on libido and erectile function, but also on bone density. You can see here if you start from a 3.0 mcg/dL of baseline concentration, the effect on libido and erectile function is seen very, very fast, but the effect on bone density on adipose tissue is a little bit slow to appear. As you increase testosterone concentrations you increase also side effects, so you have to be wise while administering testosterone in the long term.
Another aspect that is very important is the mood changes induced by testosterone replacement therapy. These are the results of our study in which we demonstrated after a short term administration, three months of testosterone gels, that depression improves, the AMS both psycho and somatic domains improve, while intercourse satisfaction and overall satisfactions at the IIEF were showing the trend to increase without significance, probably due to the small cohort of subjects. There were only 20 subjects treated with testosterone placebo respectively.
How and when to use testosterone replacement therapy?
We all know that esters are available in the market and any one of you is familiar with those preparations; propionate 10 to 25 mg two to three times a week, enanthate 200 to 250 mg every two to four weeks, cypionate 200 mg every two to four weeks. Very recently, as suggested by the prior symposium yesterday, there has been a new release, the undecanoate intramuscular. There is a very safe and efficacy testosterone preparation that is administered once every twelve weeks. Then we have topical testosterone esters, patches, gels and then buccal testosterone that is under review by the European Control Systems.
What about replacement therapy and what about treating the patients? We suggest two kinds of approach. The conservative approach must commence in a subject with overt type of hypogonadism, suggests you to achieve a target goal level of testosterone of between 3.0 and 3.5 mcg/L. Then there is another approach, the interventional approach that suggests you to treat all patients with total testosterone less than 3.5 mcg/L and to achieve a target level of 4.6 to 6.0 mcg/L that is the normal adult reference range for subjects.
So what are the indications for these two different kinds of approaches? You have to look at the side effects. First of all I want to show you in the slide that by using testosterone undecanoate you can easily reach the upper level reference range level of the adult in the normal male very easily, then compared to gels or intramuscular esters, because undecanoate gives you the opportunity to stay in the higher range.
What about side effects? In the left side of the slides you see that testosterone enanthate and undecanoate are comparable in terms of safety on PSA. There are small differences but not significant differences, and this is paralleled by the prostate volume as evaluated by transrectal ultrasonography. You see that the undecanoate preparations give a more pronounced rise in prostate volume but not significant. This makes testosterone undecanoate a safe preparation.
What about erythropoiesis? The same, we can say that testosterone enanthate and undecanoate are comparable in terms of side-effects on erythropoiesis.
This is the statement, testosterone and prostatic growth, what about prostate cancer in treated patients? There has been no conclusive evidence despite different epidemiologic studies aiming to demonstrate a relationship between testosterone, higher testosterone level, and the presence of prostatic cancer. There is no evidence, so we can state that at the moment we have no proof of fact that testosterone may induce prostatic growth or cancer.
In conclusion, how can we monitor patients? We suggest monitor patients under testosterone replacement therapy initially every three months and then every six months, with digital rectal examination and blood pressure monitoring, PSA evaluation, haematocrit and complete lipid assessment, then to evaluate testosterone, DHT and oestrodial levels under treatment. What are the warnings? Warnings are especially an increase in PSA higher than 1.5 ng/mL per year or 0.75 ng/mL per year over a two-year period or a PSA higher than 4.0 ng/mL, an increase in haematocrit level above 52 percent or a significant rise in blood pressure of the patients.
Audience Question: Now is that all of these effects of hypogonadism occur when they are below 300, or some effects will start, say one effect will start, at 500, the other at 400, another would start at 300. Have studies been done to show that there is a gradation in terms of the level of testosterone and the various effects that we have been talking about? That is number one.
Perhaps I was going very fast on my slides, but I showed you in the meta-analysis studies that there is a threshold below which you can easily start testosterone replacement.
The threshold is 7 nmol/L between 7 and 12 nmol you may have significant effects on all parameters evaluated; I mean libido, erections, and also mood depression and disorders related to mood, osteoporosis too. So probably I was going fast on those slides, but the meta-analysis is a kind of study which summarises your question. And the answer is yes, you have a cut-off. The cut-off is probably 10 nmol/L or 10 to 11 nmol/L.
Audience Question: I am interested to know that has it been advised to give testosterone replacement treatment to chronic renal failure patients with anaemia who routinely require erythropoietin. Is there a role of testosterone replacement in them so that we can utilise its side effect of haematopoiesis? And we may just give testosterone and we may not have to give erythropoietin supplementation in renal failure patients with anaemia?
Dr. Aversa: Personally I have no experience with chronic renal failure patients. But it is reported in the literature a positive effect of testosterone on erythropoiesis and so you can treat patients with testosterone, even patients with chronic renal failure and expect a good result.
Audience Question: When do you order the test? What are your indications in a man to order bone density tests? We do that routinely all the time.
Dr. Aversa: As an endocrinologist that I am, I usually perform DEXA in all patients with overt type hypogonadism, so there is no cut-off with testosterone. I do therefore investigation of their bone density depending only by the presence of hypogonadism. Then, after exclusion of the presence of osteoporosis, I can go forward and looking for other effects of hypogonadism. Osteoporosis is present in many patients with hypogonadism but not in all, so you have to exclude it in all patients with osteoporosis, in my opinion.
Audience Question: Would you comment a little bit about vasodilator effect of testosterone, on cavernosal arteries, about the mechanism? And second part, does this effect occur even after acute administration of testosterone?
Dr. Aversa: Thank you for the question. Dr. Channer has shown you before my presentation that testosterone as an acute vasodilator effect we didn’t investigate the acute effect of testosterone cavernosal arteries. We did look at the chronic effects, the short-term administration is consistent with a non-genomic effect because one month is not enough to release it genomic effect, I mean mediated by the androgen receptor. So my concept, my opinion, is that this is a non-genomic effect. But there is a vasodilator effect on cavernosal arteries, both in men with testosterone baseline levels in the grey zone as I told before between 10 and 12, and in men with levels below 10 nmol/L. The lowest is the testosterone at baseline and the highest is the effect on cavernosal arteries.
Audience Question: I want to have your comment about prostate safety because it seems that we heard yesterday that we are more on the urology community, more aggressive on PSA velocity, means that less than three years of treatment when the velocity is more than 0.5 a year. We should be aware of something going on and not 0.75? And if what I hear is more than three years of treatment if it is 0.2. So can you comment about this difference of the PSA velocity for the surveillance of the treatment?
Dr. Aversa: Yes, thank you for the question. The urology community is more aware of the side effects of testosterone of TRT of course, than the endocrinologist community. With this I don’t want to say that as an endocrinologist I do not look at the prostate size or the prostate PSA velocity. The cut-off that I have proposed are reported in a paper of the British Journal of Urology International, a review paper and reports a consensus statement. But, I believe that growing attention is given to the prostate PSA velocity, and I believe that the more strict we are with PSA velocity, the less side effects of testosterone we will see in the prostate glands. I do agree with you that we can be more severe in considering the PSA velocity than the one I have proposed.
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