Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010

Abstract

Aim: An analysis of variations in diagnosing and treating testosterone (T) deficiency between different regions of the world in 2006 was repeated in 2010. Methods: Physicians were interviewed in Germany, Spain, the United Kingdom, Brazil and Saudi Arabia about (1) reasons to use/not to use T. (2) safety (prostate pathology) and other concerns in the decision not to provide T treatment. (3) the actual usage of T preparations for treatment of erectile dysfunction (ED). Results: More men were treated with T in 2010. ED and lack of libido (2006) but also depression and obesity (2010) were regarded as symptoms of T deficiency. For 70% of physicians, severity of complaints was more significant than the laboratory value of T to prescribe T, more so in Germany (96%) than in Spain and Saudi Arabia. Concerns about prostate disease remained strong and, therefore, 11% of eligible patients did not receive T. PDE-5 inhibitors are more often combined with T in 2010 for ED. Conclusion: More appropriate studies and more education of physicians are needed on diagnosing T deficiency, on the role of T in ED and on the evidence-based relative safety of T treatment.

Keywords::

• Attitudes
• diagnosis
• regional difference
• side effects
• testosterone
• treatment

Introduction

In an earlier study, carried out in 2006, we analysed variations between different regions of the world in diagnosing and treating testosterone (T) deficiency [1]. In that study, physicians were interviewed in Germany, Spain and the United Kingdom, in Brazil, in Saudi Arabia and South Korea. In the study in 2006, the following items were addressed: (1) reasons/concerns to prescribe or not to prescribe T. (2) what category of testosterone−deficient patients would not receive T on the basis of these concerns. (3) the role of concerns about prostate pathology in the decision not to provide T treatment. (4) Further, with the advent of highly efficacious phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of erectile dysfunction (ED), treatment of ED with T has declined but there is a new appreciation for the role T can play in the management of ED. So, the actual usage of T preparations for treatment of ED was assessed. From the 2006 study, it appeared that between 5–10% of consulting patients suffered from T deficiency. The fear of physicians to induce prostate problems, in particular prostate cancer, with the administration of T to elderly men, was very powerful. About 68% of physicians associated the use of T by elderly men more with risks than benefits, more so in Europe than elsewhere. This fear was so pervasive that about 35% of men eligible for T treatment actually did not receive treatment. The prescription of phosphodiesterase type 5 inhibitors (PDE-5Is) featured very prominently in the treatment of ED. Of patients suffering from ED, 18–29% actually did have T deficiency which was not always treated. The study concluded that world-wide physicians required more education on diagnosing T deficiency, on new insights in the role of T in ED and on the relative safety of T treatment. The present study was carried out to analyse whether there were significant changes in the items mentioned above comparing the findings in 2010 with those in 2006.

Subjects and methods

The present study was carried out in April and May 2010. Physicians were approached whether they consented to a structured interview over the telephone, using a quantitative questionnaire for a duration of 30–40 minutes. The selection criteria for approaching physicians for participation in the study were the nature of their clinical practice (sufficient number of patients to allow a meaningful assessment of the research questions, sufficient number of patients with ED and/or prostate pathology to make a balanced decision to treat or not to treat, and being an initiator of T therapy in hypogonadal patients).

In each of the countries, a total of 432–2878 physicians were contacted, and between 7% and 50% were interested in participation. Eventually, in each country 50–80 physicians were eligible on the basis of the above selection criteria and could actually be interviewed. With regard to medical specialty, a total of 229 urologists, 84 endocrinologists and 40 primary care physicians were interviewed amounting to a total of 353 physicians.

The questions asked to physicians were the same as in the survey of 2006, except that physicians were not questioned on their diagnostic approach to men clinically suspected to be hypogonadal.

Statistical analysis

To determine whether there were statistically significant differences between the survey of 2006 and of 2010, the t-test was used. Significance was calculated at the p < 0.01 and p < 0.05 level.

Results

Patient distribution and characteristics

The findings of the study of 2006 [1] are presented in brackets following the data of the present study in 2010. Of the patients seen by the selected physicians, an average of 11% (in 2006: 8%) suffered from testosterone deficiency. There were differences between countries: an average of 12% (in 2006: 7%) of the patients the physicians see in Europe and 18% (in 2006: 9%) elsewhere were T deficient. Notably, Brazil with 24% and Saudi-Arabia with 13% scored highest and Germany lowest with 8%, UK with 9% and Spain with 20% each. Most men diagnosed with testosterone deficiency were >45 years of age: 77% (in 2006: 72%) in Europe and 75% (in 2006: 69%) elsewhere. Of the men diagnosed with testosterone deficiency, 47% (about 66%) actually received testosterone treatment. If this figure is broken down to age categories, 25% (36%) of men were <45 years and 75% (64%) were men >45 years (Figure 1).

Figure 1.  Distribution of patients with testosterone deficiency.

If the percentage of men diagnosed with T deficiency who actually receive T treatment is divided into men <45 years and men >45 years, then more men actually received T treatment in 2010 compared to 2006, though differences were not large: Of the men with T deficiency <45 years, 71% received T treatment in 2006 and 74% in 2010. Of the men >45 years, 65% received T treatment in 2006 and 73% in 2010. The reasons why men under 45 years did not receive T treatment were that patients did not find it necessary (10%) or opted for alternative treatment (16% in 2010 compared to 7% in 2006). Concerns of patients about T treatment remained largely the same in 2010 (16%) and 2006 (18%) The reasons why men >45 years with T deficiency did not receive T treatment were concerns about prostate pathology (24% in 2010 and 20% in 2006). The factor age as a reason not to undergo treatment with testosterone was more important in 2010 (16%) than in 2006 (3%).

Diagnosis of testosterone deficiency

Laboratory diagnosis

As expected, laboratory measurement of total testosterone figured prominently: 82% (in 2006: 76%) regularly and 17% (in 2006: 19 %) sometimes. Measurement of free testosterone was reported to be performed regularly by 32% (in 2006: 46%) and sometimes by 36% (in 2006: 30%). Measurement of the main carrier protein of testosterone: sex hormone binding globulin (SHBG) was regularly done by 29% (in 2006: 32%) of the respondents and sometimes by 45% (in 2006: 39%). Free testosterone can be calculated by introducing the value of total testosterone and SHBG into a mathematical model and this was regularly done by 37% (in 2006: 29%) and sometimes by 43% (in 2006: 31%) of the respondents. The Free Androgen Index which is calculated by dividing plasma total testosterone by plasma SHBG (a not very accurate index of free testosterone levels) was used by 23% (in 2006: 26%) regularly and sometimes by 53% (in 2006: 28%) of the respondents. Luteinizing hormone was regularly measured: 32% (in 2006: 62%) and sometimes in 36% (in 2006: 30%).

Clinical symptoms

A following question was: What do you consider the main symptoms of testosterone deficiency? (Responses were unprompted). The results are presented in Figure 2.

Figure 2.  Main symptoms of testosterone deficiency − unprompted − total.

It appears that sexual symptoms are predominant, ED: 63% (in 2006: 55%) more so than lack of libido: 53% (in 2006: 72%). Fatigue was mentioned by 45% (in 2006: 38 %) of the respondents. Other symptoms associated with T deficiency were loss of power: 13% (in 2006: 13%), depression: 26% (in 2006: 9%), weight gain: 16% (in 2006: 6%) and loss of hair/reduced body hair: 16% (in 2006: 4%).

Reasons to start testosterone treatment

When asked about the decision to prescribe testosterone the following answers were provided. An average of 70% of physicians was inclined to give greater weight to symptoms of testosterone deficiency (in 2006: 72%) than to laboratory values of testosterone (27%). There were remarkable differences by country. In Brazil (62%), the UK (63%), and particularly Germany (96%) were prompted rather by clinical symptomatology, while these figures were 36% for Saudi-Arabia and only 7% for Spain, where the laboratory outcome played a more dominant role.

The reasons to provide T treatment varied considerably country by country. Responses were unprompted. Improvement of sexuality was very prominent in Brazil (48%) and improvement of libido was also significant (44%) in Saudi-Arabia (30%) and Spain (42%). Improvement of erectile function was important in Saudi-Arabia (29%) and Spain (49%). General symptoms (24%) and their severity (25%) were influential in Germany. Low testosterone levels were motivations in Germany (21%), Saudi-Arabia (28%) and the UK (46%).

Concerns about potential side effects

Somewhat unexpectedly, in spite of much more information on side effects of T, significantly more physicians expressed concerns about side effects of T treatment in 2010 (78%) than in 2006 (54%). Concerns about prostate cancer (55% in 2010 and 51% in 2006) were still very alive. Further, concerns about cardiovascular disease: 17% in 2010 and 4% in 2006, risk of all kinds of cancer: 10% in 2010 and 4% in 2006 and effects on erythropoiesis (polycythemia): 9% in 2010 and 4% in 2006 were reported.

In response to the question: what are your considerations to initiate or not to initiate testosterone treatment even though clinical and laboratory diagnosis warrant testosterone treatment, the main reasons against a testosterone therapy were predominantly prostate related, like induction/risk of prostate cancer (51%) but less prominently than in 2006 (66%). But reasons against T treatment with regard to other risks were stronger in 2010 than in 2006. Many more physicians saw reasons for T treatment in 2010 than in 2006: improvement of ED rose from 11% in 2006 to 20% in 2010, improvement of sexuality from 2% to 17%, general symptoms from 12% to 15% and severity of symptoms of T deficiency from 1% to 17, but improvement of libido and of quality of life featured less prominently in 2010: respectively from 20% in 2006 to 10% in 2010 and from 17% to 12%.

Duration of T treatment

Data are presented in Figure 3. Patterns of prescribing T for the short term or longer term had not changed from 2006 to 2010, but reasons for not treating lifelong had changed between 2006 and 2010, and costs and patients’ own choice had become more prominent. In 2010, improvement of symptoms and of T levels was much more important than 2006 in the decision not to treat lifelong.

Figure 3.  Distribution of therapy duration − total (weighted).

With regard to duration of treatment with parenteral TU, intended lifelong treatment was 33% and 67% used it for a limited period, mostly between 10 and 48 months. A switch from one kind of T treatment to another was noted in 21%. In 49% of patients, there were interruptions in the administration of T. The pattern for T gel was not very different, but duration of treatment was often shorter than with the injections of TU.

Patterns were not very different between use of T gel and parenteral TU.

Testosterone for treatment of ED

In the present study, more attention was given to the role of testosterone in the treatment of ED. When patients do not receive T treatment in spite of the diagnosis T deficiency, it was motivated by fear that T treatment will induce/aggravate prostate pathology, and even worse, prostate cancer and it was as strong in 2010 as it was in 2006.

Of patients with ED, 30–35% of patients fail to respond to treatment of with PDE-5Is, possibly associated with testosterone deficiency [2]. The pharmacological activity of PDE-5Is seems androgen-dependent, which is well documented in animal experimentation [3]. Also in humans, the expression of PDE-5 appears androgen-dependent [4]. In men with ED and low or low-normal testosterone not responding to PDE-5Is [5,6], addition of testosterone appeared helpful.

The percentage of patients suffering from ED per country ranged from 5%–13%. Of these patients between 66%–87%, receive medical treatment. In men complaining of ED in 66–72%, serum T is routinely measured. In this regard, there was no significant change between 2006 and 2010.

With regard to reasons for not measuring T in men with ED, consideration of costs for the determination of T were significantly more important in 2010 than in 2006. Also more physicians deemed it unnecessary or made it dependent on symptoms of the patients. Remarkably Germany scored low (55%) with measuring T levels in men with ED as compared to the other countries where T was measured in 89%–97%.

Figure 4 presents the percentage of patients diagnosed with ED who actually have T deficiency varying from 41% to 63%.

Figure 4.  Distribution of erectile dysfunction patients with testosterone deficiency.

While treatment with PDE-5Is remains the mainstay of treatment of ED, the combination with T is gaining acceptance and monotherapy with T remains constant. Even though men with ED are diagnosed with T deficiency, in 2010, compared to 2006, they are less often treated with T as monotherapy but rather with the combination of PDE-5Is and T: in 2010: 23% and in 2006: 13%. Monotherapy with PDE-5Is was more frequent in 2010 (44%) compared to 2006 (34%).

With regard to treatment options for men in 2006 and 2010, there were remarkable differences in the different countries which were surveyed. In Saudi-Arabia, Spain and the UK, the combination of PDE-5Is with T is gaining traction in 2010, while in Germany monotherapy with PDE-5Is has become more frequent. In the UK, monotherapy with T has become more frequent in 2010 compared to 2006. This pattern is not very different if only men with T deficiency are considered.

The response rate to treatment of the various treatment modalities in 2010 was compared to 2006 and treatment success of monotherapy with PDE-5Is and of the combination of PDE-5Is and T had improved (Figure 5).

Figure 5.  Response rate for erectile dysfunction therapy − options in hypogonadal patients − total.

Figure 6 presents the success rates per treatment modality by country and it appears that the combination of PDE-5Is with T is very successful. T monotherapy was in all countries at least in 40% of cases successful.

Figure 6.  Overall responding rate of therapies for erectile. Dysfunction − treatment in hypogonadal patients − total.

Discussion

This study compared attitudes of physicians to medical problems potentially related to T deficiency and how these are diagnosed and treated in 2010 compared to 2006 in different countries in different parts of the world.

ED and lack of libido remained, in the perception of physicians, the main symptoms of T deficiency. But compared to 2006, the number of symptoms mentioned in this context significantly increased; now also depression and obesity were regarded as potentially associated with T deficiency. Overall, 70% of physicians considered severity of complaints to be more influential on their decision to prescribe testosterone therapy than the actually measured T levels. This was most pronounced in Germany (96%), while in Spain and Saudi Arabia determination of T levels was considered most important. This approach of attributing greater value to clinical symptomatology may make sense. It appears that men are capable of sensing signs and symptoms of testosterone deficiency at for them specific levels of plasma testosterone [7,8]. These publications demonstrate that in individual men there is not a single level of testosterone concentrations at which the spectrum of complaints of testosterone deficiency manifest themselves but for each symptom, a different threshold level of testosterone exists. These thresholds vary between men. These observations call for a diagnosis of testosterone deficiency that combines clinical symptoms of testosterone deficiency with laboratory diagnosis.

Physicians’ knowledge about at what T level to start T treatment has advanced considerably since 2006: commonly T treatment is started at a T level between 6 and 12 nmol/l, or 3–4 ng/ml. But the threshold value varies between countries. Compared to 2006, physicians in 2010 saw considerable more reasons to start T treatment, while concerns about prostate cancer were somewhat less prominent but certainly still present and remain significant. This concern is most pronounced in Brazil (80%) and Saudi Arabia (78%) and least in Germany. About 11% of patients do not receive T therapy because of the presumed risk of prostate cancer and 7% do not receive therapy because of the presumed risk of lower urinary tract symptoms. Other concerns were stated now, such as polycythemia and cardiovascular disease.

Nearly 75% of all patients with T deficiency do receive testosterone therapy which is approximately true across all countries. Treatment rates in 2010 had increased significantly compared to 2006, mainly in patients >45 years with late onset hypogonadism. The reimbursements of costs related to disease and medical drugs may have impacted on the outcome of the survey.

Significantly more physicians express concerns about side effects of T treatment in 2010 than in 2006. There are now authoritative guidelines to educate physicians on responsible use of T, particularly in elderly men [9–11]. But the final verdict on the safety of long-term use of testosterone in elderly men is not known. And, therefore, all elderly men receiving testosterone should be monitored carefully following recommendations [9,10]. Two meta-analyses [12,13] do not provide an alarming picture of the safety of testosterone treatment with regard to mortality, prostate, or cardiovascular outcome. There are new outlooks on the relationship between testosterone and prostate cancer [14,15] but caution should guide physicians in their approach to testosterone treatment.

Main reasons given for non-treatment of patients >45 are risk of prostate cancer and patients’ own concerns. For younger patients, alternative treatments (sports and diet) were more often recommended in 2010 compared to 2006 and gained importance. Indeed, exercise and diet if resulting in weight loss may result in a rise of serum T levels [16–18]. Average treatment duration of parenteral TU is about 30 months. Approximately, 66% receive parenteral TU only for a limited period, while approximately 33% will intend to use it lifelong. About 18% switch to another form of T administration. Discontinuation of therapy is somewhat higher for the T gel than for depot injection with TU. Data in the literature suggest that subjective benefit is an important element to continue T treatment for at least 12 months [19]. In that study, approximately 66% of patients experienced benefits, noted after 3 months. A recent study provides reliable information when treatment effects can be expected to occur and when they are about maximal [20].

With regard to T therapy in ED patients: In 2010, T levels are routinely measured by 66% of all physicians participating in this survey which is a slight decrease compared to 2006 (72%). The high costs were the main reason not to measure T levels routinely (significantly increased since 2006).

Around 6 out of 10 ED patients whose T levels are measured suffer from T deficiency. These patients most frequently receive PDE-5Is monotherapy followed by combination therapy of PDE-5Is and T therapy. This survey shows that the combination of PDE-5Is with testosterone therapy produces the highest success rate (66%) and this combination is significantly more prescribed in 2010 compared to 2006.

In summary, there were shifts in the concepts of clinical complaints associated with T deficiency and its diagnosis and treatment. Physicians see a wider role of testosterone than sexual functioning per se. Over the last 5 years, several guidelines have appeared for a responsible use of T [9,10], also in elderly men. Clearly, more education about responsible use of T is necessary. But more importantly, education should be based on solid studies showing the benefits of restoring testosterone to normal levels, not only at young age but also later in life. The costs for such studies are prohibitive. For the pharmaceutical industry, testosterone is a relatively small product not generating the money, for instance, cardiovascular or anti-diabetic drugs do, and therefore funding for studies is accordingly limited.

Declaration of interest: The survey was performed by Genactis GmbH, Cologne, Germany, and funded by Bayer Pharma AG, Berlin, Germany. LG has received compensation for lectures by Bayer Pharma AG Berlin, Germany. HB has received compensation for lectures by Bayer Pharma AG Berlin, Germany and Ferring Pharmaceuticals.