Clinical experience with Andriol® Testocaps®– The first Austrian surveillance study on the treatment of late-onset hypogonadism

Abstract

Objective. The objective of this study was to document the efficacy and tolerability of the new formulation of Andriol® Testocaps® in the treatment of late-onset hypogonadism in a clinical practice setting.

Methods. The primary inclusion criterion was symptomatic testosterone deficiency, as confirmed by laboratory testing (morning total testosterone <12 nmol/L) on two separate occasions. The study was performed in 43 centres in Austria and a dosage of oral testosterone undecanoate of 2×80 mg/day was used for three months. The ADAM questionnaire, the AMS scale and the SF-36 questionnaire were administered by the patients and specific questions were asked to the prescribers.

Results. A total of 189 patient report forms and 185 doctor report forms were completed. The average age of the participants was 54.7 ± 12.3 years and average treatment duration was 13.9 ± 2.2 weeks. Serum testosterone level increased by more than 50% from 8.7 ± 4.3 nmol/L to 13.2 ± 6.7 nmol/L (p < 0.001). Treatment improved symptoms on the ADAM and AMS scales, whereas no changes were observed on the SF-36. There were no significant effects on serum PSA levels.

Conclusion. Short-term treatment with oral testosterone undecanoate in a clinical practice setting improved late-onset hypogonadism symptoms in aging men with low testosterone levels.

Keywords:

• testosterone undecanoate
• hypogonadism
• PSA
• aging males

Introduction

According to the Massachusetts Male Aging Study, serum testosterone levels in men drop by around 1.6% per year from the age of 50 years, although this figure is subject to considerable interindividual variation [1]. Measurements recorded to date suggest that approximately 12% of men aged 50–59 years, 19% of men aged 60–69 years, 28% of men 70–79 years and even 49% of men ≥ 80 years suffer from hypogonadism [2]. In 2002, the International Society for the Study of the Aging Male (ISSAM) defined hypogonadism as documented testosterone deficiency with corresponding symptoms [3]. This clinical condition is appropriately termed ‘late-onset hypogonadism’ (LOH). Other inappropriate terms have been used in the past to describe this syndrome, e.g. ‘andropause’, ‘male menopause’ or ‘climacterium virile’. Although some of the signs and symptoms of LOH are comparable with menopausal symptoms in women, the onset of the symptoms in men is usually more subtle. In view of its insidious progression and the slow onset of the clinical symptoms of the syndrome, it is much more difficult to detect these changes in the aging male.

Androgen therapy in hypogonadal men has been shown to improve not only serum testosterone levels but also patients' symptoms. Since physicians are dealing with aging men, possible side effects have to be individually determined and discussed with the patient prior to therapy. There are several modalities of testosterone therapy available from buccal, oral, transdermal, subcutaneous and intramuscular applications.

Each treatment has its benefits and possible side effects, not identifying one medication as first line therapy in any case. Recently, the ISSAM recommended the preference for short acting androgen therapy in aging men because of its potential effect on the prostate. These include the application of buccal, transdermal and oral treatments. One advantage for oral treatment is the patient's comfort and convenience; therefore some men prefer oral administration in testosterone replacement. Andriol® Testocaps®, capsules containing testosterone undecanoate (TU) 40 mg in castor oil, a new and improved preparation for oral testosterone treatment, was launched in Austria in the fall of 2003. The innovative feature of this preparation is not the active ingredient itself, but a change in the pharmaceutical formulation of the preparation that permits long-term storage outside the refrigerator [4]. Pharmacokinetic studies with the new formulation of oral TU have shown that a dosage of 2×80 mg/day produced normal testosterone levels in most patients [5], but adequate plasma levels can only be achieved when capsules are taken with a (normal) meal for optimal absorption via the lymphatic system of the small intestine [6],[7]. However, so far it has not been studied how this new formulation works in daily clinical practice in aging men with testosterone deficiency. The purpose of this study was to document the efficacy and tolerability of the new formulation of oral TU in the treatment of late-onset hypogonadism in a clinical practice setting.

Methods

From September 2003 until January 2004, oral TU was evaluated in the treatment of hypogonadism in urological practice in the context of a national Austrian post-marketing surveillance study conducted under the auspices of the Study Group of Andrology and Sexual Dysfunction of the Austrian Association for Urology and Andrology. Why is there such a long delay in reporting the data? The primary inclusion criterion for participation in the study was symptomatic testosterone deficiency, as confirmed by laboratory testing (morning total testosterone <12 nmol/L) on two separate occasions in male patients with a minimum age of 18 years. Exclusion criteria were history or presence of prostate or breast cancer, International Prostate Symptom Score >14 points, hyperprolactinemia, erythrocytosis, hepatic or renal insufficiency, hypersensitivity to the active substance or any of the excipients and participation in any other clinical trial.

The study was performed in 43 centres in Austria and investigated the safety and efficacy of oral TU (Andriol® Testocaps®) at a dosage of 2×80 mg/day during 3 months in respect of the typical symptoms of LOH and the improvement in health and mental well-being of the patients prior to and after testosterone supplementation. Patients were informed to take their capsules after a normal meal (with a lipid content of approximately 20 g). The results of the post-marketing surveillance study are based on the subjective change in the patient's symptoms, objective serum parameters and the therapeutic assessment of the attendant urologist. The results were documented on standardized case report forms.

The Saint Louis University ADAM Questionnaire [8], the Aging Males Symptoms (AMS) questionnaire [9] and the SF-36 questionnaire were administered by the patients at baseline and at the end of treatment to determine clinical efficacy. At the end of the treatment period, the following three concluding questions were asked: (1) How has your enjoyment of life changed since the start of therapy? (2) How has your physical well-being changed since the start of treatment? and (3) How has your performance changed since the start of treatment? Possible answers were: ‘improved’, ‘deteriorated’ and ‘unchanged’. Finally, for each patient a questionnaire on the effect of treatment was administered by the treating physician. Serum trough testosterone levels and prostate-specific antigen (PSA) were measured before start of treatment and at the end of the study. Differences between baseline and treatment values of serum testosterone and PSA were statistically tested using the t-test.

Results

A total of 189 patient report forms and 185 doctor report forms were completed. The average age of the participants was 54.7 ± 12.3 years. The average treatment duration was 13.9 ± 2.2 weeks. The mean serum testosterone level increased with oral TU by more than 50% from 8.7 ± 4.3 nmol/L before treatment to 13.2 ± 6.7 nmol/L (p < 0.001) at the end of the treatment period (Figure 1).

Figure 1. Testosterone serum levels before and during treatment with Andriol® Testocaps® 2×80 mg per day.

During treatment with oral TU, the mean scores on the individual questions of the Saint Louis ADAM Questionnaire improved for all 10 questions. The most prevalent complaint was ‘reduced strength of erection’, which was present in 88% of subjects before treatment. After treatment this percentage had decreased to 30%. Before treatment ‘libido’ was decreased in 83% of patients, whereas with oral TU the prevalence was reduced to 23%. Approximately two-thirds (65%) of the men stated that they were ‘lacking in energy’ prior to treatment, this proportion dropped to 21% at the end of the study. A similarly positive trend emerged from the subjective assessments of muscle strength/stamina, loss of height, enjoyment of life and work performance (Table I). Similarly, the AMS questionnaire showed a reduction of symptoms such as irritability, nervousness, lack of energy, muscle weakness, depressed mood, erectile dysfunction and libido and during treatment in the majority of men (not presented). Finally, the SF-36 questionnaire suggested improvements in physical functioning although this was not statistically significant, whereas there was no major effect on general health status (not presented).

Table I.  Effect of Andriol® Testocaps® on the individual questions of the Saint Louis ADAM Questionnaire.

Question	Baseline	End of study
Is your sex life (libido) tailing off?	83%	23%
Do you lack energy?	65%	21%
Is your strength and/or stamina failing?	64%	25%
Have you lost height?	22%	6%
Do you feel you are enjoying life less?	49%	16%
Are you often unhappy or irritable?	29%	14%
Are your erections less strong?	88%	30%
Are you performing less well at sports?	62%	26%
Do you regularly fall asleep after meals?	25%	13%
Is your work performance getting poorer?	54%	16%

At the end of treatment, 35% of the patients stated that their performance had improved compared to the pre-treatment phase (Figure 2), 44% reported an improvement in physical well-being (Figure 3) and 45% an improvement of ‘enjoyment of life’ (Figure 4). Oral TU also improved subjective depressive symptoms that are commonly associated with hypogonadism. During the period of testosterone supplementation, the proportion of patients reporting some form of depression dropped from 29% at the initial interview to 14% by the end of the study. A similarly positive trend emerged from the self-assessment involving terms such as ‘irritable’, ‘nervousness’, ‘dejected’, ‘disheartened and sad’. In addition, the percentage of those patients who predominantly felt ‘satisfied’ steadily increased (20.5% versus 31.8%). While 39% of the patients complained of major depressive episodes at the start of the study, this figure had fallen to just 22% towards the end (Figure 5).

Figure 2. How has your performance changed since the start of therapy?

Figure 3. How has your physical well-being changed since the start of treatment?

Figure 4. How has your enjoyment of life changed since the start of therapy?

Figure 5. To what extent do you suffer from depression?

Asking physicians' perception about the effects of 3 months of testosterone treatment in their patients, most reported symptomatic improvement, ranging from 50% for performance to 67% for libido (Table II).

Table II.  Physician-administered questionnaire on the effects of Andriol® Testocaps® after three months of treatment

Question	Yes	No
Has testosterone treatment improved your patient's libido?	67%	33%
Has testosterone treatment improved your patient's joy of life?	65%	35%
Has testosterone treatment improved your patient's muscle strength/endurance?	54%	46%
Has testosterone treatment improved your patient's erectile function?	54%	46%
Has testosterone treatment improved your patient's performance?	50%	50%

Adverse events such as restlessness and sleeping problems were registered in just 6%, but these were only of slight or moderate intensity in all cases. The mean level of PSA between the initial and final investigations showed only a slight increase, from 1.06 ng/mL to 1.17 ng/mL, which was not significant (Figure 6).

Figure 6. Serum PSA levels before and during treatment with Andriol® Testocaps® 2×80 mg per day.

Discussion

The current study on the treatment of late-onset hypogonadism with a new formulation of oral TU (Andriol® Testocaps®) has aroused considerable interest among urologists in Austria. A total of 43 centres participated in the post-marketing surveillance study and a total of 189 patients were recruited. The overall results indicated that from a patient's as well as from a physician's perspective, short-term treatment with oral TU in a clinical practice setting rapidly improves subjective testosterone deficiency symptoms.

All of the therapeutic strategies to date have either been non-physiological (such as testosterone injections) or otherwise administration has only been possible via the implantation of a depot preparation after local anaesthesia (testosterone implants). While testosterone gel is certainly a possible alternative, not every man feels comfortable with the daily application of the gel. In a recent survey among Asian prescribers, treatment of late-onset hypogonadism with oral testosterone undecanoate appeared as the most popular form of androgen replacement therapy [10]. Consequently, the new formulation of oral TU represents a highly interesting therapeutic approach.

During this study it emerged that treatment with oral TU 2×80 mg per day produced a significant elevation in the serum testosterone to levels in the lower normal range. The restoration of testosterone levels within the physiological range with oral TU was also recently reported in a dose-finding study in which a dose range of 120–240 mg per day was investigated [5]. Moreover, it has been reported that the increase of serum testosterone levels with oral TU is proportional to the dose administered, making dose-titration to individual needs easy and predictable [11].

The preparation proved safe in respect of its effects on the prostate since no significant rise in the PSA level occurred and no subject had to withdraw from the study as a result of side effects including prostate cancer. The absence of a PSA increase with Andriol® Testocaps® confirms results obtained in a recently published 12-month study with oral testosterone undecanoate [12].

Since only LOH patients were included in this study, oral testosterone therapy once again determined the rapid improvement in quality of life and symptoms. As expected, the central nervous parameters (e.g. libido) reacted more promptly to the supplementation therapy than the physical symptoms (e.g. muscle strength). Other recent studies using oral testosterone undecanoate with a similar study design (but using different rating scales) also reported rapid improvement of symptoms and quality of life and sexual function [13],[14].

It should be emphasized that one of the limitations of the current study is that it did not have a placebo-controlled design. However, the objective of this trial was to obtain information about testosterone treatment in a clinical urological practice setting rather than obtaining data in an experimental scientific setting. Another limitation of the study was that follow-up period was only 3 months. In most patients, LOH symptoms will respond to testosterone treatment within a few weeks. However, when there is no subjective symptom improvement noticeable within 3 months, it has been proven difficult to maintain a patient on therapy. The limitations of the current study have been addressed in a recently finalized multicentre, randomized, placebo-controlled dose-finding study with a duration of 1 year in 322 hypogonadal symptomatic aging men of which the results are expected to become available in the course of 2007 [15].

Overall, the introduction of the new formulation of oral TU extends the arsenal of therapeutic options for testosterone replacement, and is a safe and well-tolerated dosage form.

Potential conflict of interest

This study was supported by Organon GesmbH, Vienna, Austria. Mr Geurts is an employee of NV Organon, Oss, The Netherlands, but he did not receive any additional compensation outside his normal salary. Dr Jungwirth and Dr Plas did not have any conflict of interest.

Acknowledgements

We would like to thank Mr Christian Schmidt of Organon GesmbH for his support in the development and execution of the study as well as all the physicians that participated in the study: Dr Gerd Baumgartner, Graz; Dr Reinhard Böhm, Vienna; Dr Andreas Bucher, Vienna; Dr Karl Diehl, Tulln; Dr Peter Dollezal, Vienna; Dr Peter Droschl, Graz; Dr Arno Ebner, Innsbruck; Dr Wolfgang Edtstadtler, Vienna; Dr Günther Egger, Vienna; Dr Rudolf Eidler, Vienna; Dr Werner Hechtl, Voitsberg; Dr Rudolf Holzmann, Vienna; Dr Gerhard Huber, Baden; Dr Andreas Jungwirth, Salzburg; Dr Wolfgang Kautzky, Wolfsberg; Dr Kurt Kerbl, Kirchdorf an der Krems; Dr Michael Kiesenhofer, Leonding; Dr Pavel Konecny, Stockerau; Dr Christian Kratzik, Vienna; Dr Heinz Lindemeier, St Pölten; Dr Christian Lintner, Scheibbs; Dr Georg Ludvik, Vienna; Dr Johannes Mayer, Vienna; Dr Johannes Mitterhuber, Wels; Dr Günther Petrischor, Innsbruck; Dr Eugen Plas, Vienna; Dr Hans Helmut Pusch, Graz; Dr Hans Rauschmeier, Vienna; Dr Wolfgang Schachtner, Schwarz; Dr Franz Xaver Schuster, Vienna; Dr Viktor Seklehner, Vienna; Dr Abdul Sofi, Lilienfeld; Dr Peter Sternig, Klagenfurt; Dr Gerhard Suster, Vienna; Dr Andreas Szalay, Vienna; Dr Paul Teiche, Wels; Dr Thomas Michael Treu, Vienna; Dr Harald Trummer, Graz; Dr Walter Weissenbacher, Völkermarkt; Dr Gerhard Weissteiner, Innsbruck; Dr Astrid Zeitelberger-Renz, Mistelbach an der Zaya.