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Efficacy and safety of long-acting testosterone undecanoate in men with hypogonadism in daily clinical practice

IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. Zitzmann M, Mattern A, Hanisch J, et al. J Sex Med 2013; 10(2): 579-588.

This Research News article reviews article available in full from The Journal of Sexual Medicine, via Wiley Online Library.

This prospective, observational, post-authorization surveillance study investigated the safety and efficacy of intramuscular injections of testosterone undecanoate (TU) in men with testosterone deficiency syndrome (hypogonadism) in a clinical practice setting.1 The study, conducted in 23 countries throughout Europe, Asia, Latin America and Australia, enrolled 1493 men (mean age 49.2 ± 13.9 years) with a diagnosis of primary or secondary testosterone deficiency syndrome (serum total testosterone 8–12 nmol/L for newly diagnosed treatment-naïve patients). The men received up to five injections of TU during an observation period of 9–12 months. Between the first and second injections of the agent there was an interval of 6–10 weeks, and subsequent injections were given at intervals of 12 ± 2 weeks.

The study aimed to assess treatment outcomes of male patients with testosterone deficiency syndrome who received TU under ‘real-life’ conditions, and to assess the treatment continuation rate in such patients and further confirm the safety profile of TU. Parameters of erectile function, libido, vigor/vitality, mood and ability to concentrate were assessed by physician interview using items and five-point Likert scales. Certain physical and circulatory parameters, as well as other laboratory parameters, were also measured at each injection visit.

Of the 1493 men enrolled, 72.5% were Caucasian, followed by 19.7% and 7.5% of Asian and Latin American descent, respectively. A total of 1438 and 1140 men were evaluable at baseline and at the time of the fifth injection, respectively. At baseline, mean body weight was 86.8 kg, and 54% of those enrolled had previously received androgen therapy. Mean serum testosterone (T) was 9.6 ± 7.5 nmol/L, and comorbidities included erectile dysfunction (ED), hypertension and dyslipidemia.
Key Points

  • Mean trough serum total T increased from 9.6 nmol/L at baseline to 17.3 nmol/L before the fifth injection (p<0.0001)
  • At the time of injection 5, there was a significant improvement in the overall levels of sexual desire/libido compared with baseline

    • A total of 64% of patients at baseline experienced very low/low sexual desire/libido compared with 10% at injection 5
    • The proportion of patients with a high/very high libido increased from 10% at baseline to 61% at injection 5 (overall p<0.0001)
  • Significant improvements over each injection interval were seen in the overall levels of vigor/vitality, mood and ability to concentrate (p<0.0001 for each)
  • The proportion of patients reporting moderate, severe or extremely severe ED was significantly decreased from baseline at the time of the fifth TU injection, from 65% to 19% (p<0.0001)

    • In those patients with some form of ED who did not receive concomitant phosphodiesterase type 5 (PDE5) inhibitor therapy, 56% reported a decrease from baseline in ED severity following TU therapy
    • The proportion of patients reporting a high or very high response to PDE5 inhibitor therapy increased from 35.1% at baseline to 56.6% at injection 5
  • Mean waist circumference decreased from 100 to 96 cm and the reduction was statistically significant whether or not patients had previously received androgen therapy (Figure 1)
  • A total of 35.4% of patients each, reported being very satisfied or satisfied after treatment with TU
  • Blood pressure, serum triglyceride, total cholesterol and LDL cholesterol levels were all significantly improved from baseline at injection 5 (p<0.02; Figure 2) whereas there was a slight increase in HDL cholesterol (not statistically significant)
  • Adverse drug reactions (ADRs) related to TU therapy were rare (5.8%), and only 1 was considered serious (0.1%)

    • The most common ADRs were increased hematocrit, increased PSA levels and injection site pain, all of which occurred in <1% of patients
    • Overall, ADRs were associated with treatment discontinuation in 31 patients.

What is known

Hypogonadism (testosterone deficiency syndrome), which can be defined as serum total testosterone ≤12 nmol/L and a positive score suggestive of androgen deficiency on the AMS questionnaire, is increasingly recognized as a significant health problem in aging men.2-8 Testosterone deficiency syndrome adversely impacts physical health (including loss of physical strength, loss of muscle mass, increased visceral fat leading to a higher risk for metabolic syndrome and premature death), sexual function (loss of secondary sexual characteristics, decreased libido and erectile dysfunction) and psychological health (mood changes and sleep disturbances).5 Androgen replacement therapy is the principal treatment for testosterone deficiency syndrome, and involves the administration of T at doses which aim to reproduce normal blood T levels, in order to improve exposure of androgen-dependent tissues and organs to T. In general, the better the improvement in T levels after androgen replacement therapy, the better the clinical outcomes.1 TU is an intramuscularly administered, long-acting formulation of T used as an androgen replacement therapy for men affected by testosterone deficiency syndrome. As few large-scale post-marketing surveillance studies of TU have been conducted, and no large trials evaluating the agent in Asian and South American populations have been conducted at all, this trial aimed to confirm the safety profile of TU in men with testosterone deficiency syndrome, and to evaluate the efficacy of the agent in a ‘real world’ clinical setting throughout Europe, Asia, Latin America and Australia.

What this study adds

This international, multicenter, one-arm, non-interventional, prospective, observational Post-Authorization Surveillance Study (IPASS) confirmed the safety profile of TU, and demonstrated its effectiveness in a large global cohort of patients, including those from Asia and South America.1

Mental and psychosexual function scores (libido, vigor, overall mood and ability to concentrate) were all significantly improved over the course of the study, as were blood pressure and the majority of lipid parameters examined (Figure 1). After four injections of TU, the proportion of patients with low or very low sexual desire was significantly decreased, and 89% of patients declared themselves to be satisfied or very satisfied with TU therapy. The major limitation of this study was its potential for bias; however, the large sample size somewhat reduces the chance of this.

Figure 1: Reduction in waist circumference during 12 months of testosterone undeconate therapy

Figure 2: Mean improvement in lipid parameters during treatment with long-acting testosterone undeconate


1. Zitzmann M, Mattern A, Hanisch J, et al. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med 2013; 10(2): 579-588.
2. Ullah MI, Washington T, Kazi M, et al. Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res 2011;43(3):153-164.
3. Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care 2011;34(7):1669-1675.
4. Bassil N, Morley JE. Late-life onset hypogonadism: a review. Clin Geriatr Med 2010;26(2):197-222.
5. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55(1):121-130.
6. Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men. Am J Med 2007;120(10):835-840.
7. Traish AM, Miner MM, Morgentaler A, et al. Testosterone deficiency. Am J Med 2011;124(7):578-587.
8. Saad F, Aversa A, Isidori AM, et al. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol 2011;165(5):675-685.

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