Abstract
Sexual activity, sexual desire, and mood decrease in men with low testosterone levels. The Testim® Study of Testosterone Androgen Response Time (START) explored the time to response in sexual activity, desire, and mood following testosterone replacement therapy with Testim for 30 days in 638 hypogonadal men. Response in sexual activity, desire, and mood all improved relative to baseline within the first week of Testim therapy. Patients reached a maximal response by the end of 2 weeks of therapy and maintained the response through 4 weeks of therapy. Frequency of intercourse showed a significant increase after 2 weeks of Testim therapy. Both measures of positive mood and negative mood improved significantly, beginning with the first week of therapy and reaching and maintaining a maximal response at the second week.
Key words: Testosterone gel, Hypogonadism, Sexual function, Mood
In men, testosterone levels decrease with advancing age. Accompanying the decline are a number of negative changes in organs and functions, including a decrease in muscle mass, decrease in muscle strength, decrease in bone density, decrease in energy levels, impaired mood, increase in body fat mass, increase in the incidence of osteoporosis and fracture rates, increase in erectile dysfunction, and decline in quality and quantity of sexual thoughts and enjoyment.1 Hypogonadism has also been associated with other comorbidities, such as erectile dysfunction. Dr. A. Guay and colleagues2 reported that at the Lahey Clinic in 1999, approximately 25% of the men with erectile dysfunction also reported a loss of sexual desire in conjunction with erection and/or ejaculation problems.
Men with low testosterone levels have been shown to respond to testosterone replacement therapy in several clinical studies.3,4 The restoration of testosterone concentrations to normal levels will maintain or restore male sexual characteristics, sexual behavior, energy, mood, and muscle mass, and will improve bone density. In 1 placebo-controlled study, significant improvements compared with placebo were seen after 3 months of therapy with Testim® 1% gel (Auxilium Pharmaceuticals, Inc., Norristown, PA) in sexual desire, sexual motivation, sexual performance, and spontaneous erections, and in lean body mass, fat mass, and percent fat.5 Improvements in sexual function were seen in as little as 1 month of therapy.5
The START investigation was designed to determine at what point daily treatment with Testim 1% gel began to have an impact on sexual function and mood in a large cohort of hypogonadal men. Data on sexual function and mood, based on a validated questionnaire (Figure 1), were obtained through the daily use of an interactive voice response (telephone) system.
Figure 1.
Sexual activity/mood questionnaire. Adapted with permission from Lee KK et al.6
Subjects and Methods
Subjects
A total of 638 men were treated with Testim for up to 30 days in a multicenter, open-label, single-group study.
Study Drug
All patients had a screening total testosterone level ≤ 300 ng/dL and had not received any testosterone replacement therapy for the prior 6 months. Except for hypogonadism, the men were in generally good health. All patients received Testim 1% gel; each tube of the agent contained 50 mg of testosterone. All patients began with 1 tube of Testim per day and could increase to 2 tubes at the discretion of the investigator.
Study Design
This was a multicenter, open-label study in male subjects with serum testosterone levels ≤ 300 ng/dL. Serum testosterone levels, prostate-specific antigen, and physical examination were obtained during the screening period. Patients completed a sexual function and mood self-report diary for a 1-week baseline period before initiation of treatment with Testim. Patients applied Testim for 30 days and continued to complete the diary on a daily basis. Patients had a follow-up visit after the end of the 30 days.
Methods
Sexual functioning and mood assessments were based on a validated self-report daily diary6 that collected information on sexual desire, day and nighttime spontaneous erections, intercourse, sexual motivation, sexual enjoyment, satisfaction with duration of erection, and positive and negative mood parameters (Figure 1). Sexual desire, sexual enjoyment, satisfaction with the duration of erection, and positive and negative mood parameters were assessed on Likert-type scales (scores 0–7) and were calculated as an average weekly score. Intercourse and spontaneous erections (day and nighttime combined and nighttime alone) were calculated as the number of days in a 7-day week during which the events occurred. A composite sexual performance score was calculated based on occurrence of intercourse, masturbation, erection, orgasm, and ejaculation. A composite sexual motivation score was calculated based on occurrences of certain events related to anticipation of sex, sexual daydreams, and interactions with other people.
Statistical Analysis
The changes from baseline to each week of treatment were calculated for sexual desire, sexual performance, sexual motivation, spontaneous erections, sexual enjoyment, and satisfaction with the duration of the erection and were analyzed with a 1 sample t-test. The frequency of intercourse and nighttime erections each week was summarized. In addition, the changes in weekly frequency of intercourse and nighttime erections were summarized as “decreased frequency,” “no change,” and “increased frequency” and analyzed with Bowker’s test of symmetry (an extension of the McNemar’s test for repeated binary outcomes). All tables present values as mean ± standard deviation.
Subjects
The mean age was 52.7 years (± 11.9, range 18–86; 17.4% were 65 years or older), with mean morning serum testosterone at entry of 204 ng/dL (± 71). Eighty-nine percent of the patients applied 1 tube of Testim per day for the duration of the study; 11% applied a combination of 1 and 2 tubes per day.
Sexual Function
Table 1 presents the average score for the baseline week and weeks 1–4 for sexual desire, sexual motivation, spontaneous erections (daytime and nighttime), sexual performance, sexual enjoyment, and satisfaction with duration of erection. All parameters showed a significant increase from baseline by the end of the first week and generally reached a maximal response by the end of the second week, which was maintained for the remainder of the month of therapy with Testim.
Table 1.
Sexual Function
| Baseline | Week 1 | Week 2 | Week 3 | Week 4 |
|---|---|---|---|---|
| Sexual desire (0 = none, 7 = very high) | ||||
| 2.0 ± 1.4 | 2.6* ± 1.5 | 3.0* ± 1.6 | 3.1* ± 1.6 | 3.2* ± 1.6 |
| Sexual motivation (# days per week) | ||||
| 1.6 ± 1.3 | 1.9* ± 1.5 | 2.1* ± 1.7 | 2.2* ± 1.7 | 2.2* ± 1.7 |
| Spontaneous erections (# days per week) | ||||
| 0.7 ± 1.1 | 1.1* ± 1.5 | 1.3* ± 1.6 | 1.3* ± 1.7 | 1.2* ± 1.7 |
| Sexual performance (# days per week) | ||||
| 0.9 ± 1.1 | 1.1* ± 1.2 | 1.3* ± 1.3 | 1.3* ± 1.3 | 1.3* ± 1.2 |
| Sexual enjoyment (0 = none, 7 = very high) | ||||
| With partner 4.0 ± 1.5 | 4.4* ± 1.5 | 4.8* ± 1.4 | 4.9* ± 1.4 | 4.9* ± 1.4 |
| Without partner 3.3 ± 1.4 | 3.6† ± 1.4 | 4.0* ± 1.5 | 4.0* ± 1.5 | 4.1* ± 1.5 |
| Satisfaction with duration of erection (0 = not satisfied, 7 = very satisfied) | ||||
| 3.1 ± 1.8 | 3.4* ± 1.8 | 3.7* ± 1.8 | 3.8* ± 1.8 | 4.0* ± 1.8 |
P < .0001 versus baseline.
P < versus baseline.
Because the data were collected daily, it is possible to see how rapidly the improvements presented in Table 1 occurred. As illustrated in Figure 2, sexual desire increased rapidly within the first 2–3 days and continued to increase for the first 2 weeks; the increase began to stabilize thereafter. A similar pattern was seen for the other parameters.
Figure 2.
Sexual desire.
Because nighttime erections are probably more clearly related to androgenic action than are daytime erections, the occurrences of nighttime erections alone were explored in greater detail. Table 2 presents the distribution of the number of days each week the patients reported nighttime erections. During the baseline week, slightly more than half the patients (57%) reported no spontaneous nighttime erections whereas approximately one-fourth of the patients (26%) reported spontaneous nighttime erections 1 to 2 times during the week and 17% of the patients reported 3 or more nights with spontaneous nighttime erections. By the end of 4 weeks of therapy with Testim, the percentage of patients who reported spontaneous nighttime erections 3 or more times in a week had increased to 28%, with corresponding decreases in the other 2 categories.
Table 2.
Percentage of Patients with Spontaneous Nighttime Erections in a Week
| Week | 0 Times, % | 1–2 Times, % | ≥3 Times, % |
|---|---|---|---|
| Baseline | 57.3 | 25.9 | 16.8 |
| 1 | 51.4 | 25.8 | 22.8 |
| 2 | 50.2 | 22.4 | 27.4 |
| 3 | 46.8 | 25.5 | 27.7 |
| 4 | 52.1 | 19.9 | 28.0 |
An additional analysis classified each patient as to whether he experienced an increase in the number of nights with nocturnal erections during a treatment week relative to his baseline, no change in the number of nights, or a decrease in the number of nights. Approximately one-third of the patients reported more nights with nocturnal erections during each of the 4 treatment weeks than during the baseline week (Table 3). The number of men with increases was significantly more than the number with decreases during each of the 4 weeks with Testim.
Table 3.
Distribution of Changes from Baseline in Weekly Occurrences of Spontaneous Nighttime Erections
| Week* | Decreased Frequency, % | No Change, % | Increased Frequency, % |
|---|---|---|---|
| 1(P =.0074) | 20.4 | 48.3 | 31.3 |
| 2 (P =0008) | 17.9 | 48.1 | 34.1 |
| 3(P =0138). | 19.5 | 43.8 | 36.7 |
| 4(P =005) | 19.4 | 45.8 | 34.9 |
P based on Bowker’s test of symmetry.
The sexual performance score was a composite of all sexual activity (intercourse and masturbation) and also incorporated some indication of the success of the sexual activity (occurrence of an erection, ejaculation, or orgasm). A second analysis of sexual activity focused only on the occurrence of intercourse during the week for those days a partner was available. During the baseline week, more than half the patients (58%) reported no intercourse during the week whereas approximately a third (35%) reported intercourse on 1–2 days during the week and 6% of the patients reported intercourse on 3 or more days during the week (Table 4). The percentage of patients who reported intercourse on 3 or more days in a week more than doubled, with an increase to 15% by week 2 of treatment with Testim.
Table 4.
Percentage of Patients Having Intercourse in a Week
| Week | 0 Times, % | 1–2 Times, % | ≥3 Times, % |
|---|---|---|---|
| Baseline | 58.3 | 35.4 | 6.3 |
| 1 | 57.6 | 32.6 | 9.8 |
| 2 | 46.5 | 38.5 | 15.0 |
| 3 | 49.4 | 35.5 | 15.1 |
| 4 | 47.7 | 38.7 | 13.6 |
An additional analysis classified each patient as to whether he experienced an increase in the number of days of intercourse during a treatment week relative to his baseline, no change in the number of days, or a decrease in the number of days. By the end of 4 weeks of Testim, approximately 4 out every 10 men (39%; Table 5) reported an increase of at least 1 additional day with intercourse relative to their baseline. The number of patients with increases was significantly higher than the number with decreases during each of the last 3 weeks of Testim therapy.
Table 5.
Distribution of Changes from Baseline in Weekly Occurrences of Intercourse
| Week* | Decreased Frequency, % | No Change, % | Increased Frequency, % |
|---|---|---|---|
| 1 (P=.53) | 19.2 | 57.5 | 23.4 |
| 2 (P <.0001) | 11.1 | 51.6 | 37.4 |
| 3 (P <.0001) | 13.7 | 51.0 | 35.4 |
| 4 (P =.0002) | 14.0 | 46.7 | 39.2 |
P based on Bowker’s test of symmetry.
Mood
Table 6 presents the average scores for positive mood items (alert, full of pep/energetic, friendly, well/good) and negative mood items (angry, irritable, sad or blue, tired, nervous). Positive mood items increased significantly in score, indicating improvement in positive moods. Negative mood items decreased significantly in score, also indicating improvement in negative mood. The daily profiles of the improvement in mood scores are displayed in Figure 3. As with sexual function parameters, the response was immediate and reached a maximal level within the first 2 weeks of therapy with Testim.
Table 6.
Positive and Negative Mood Scores
| Baseline | Week 1 | Week 2 | Week 3 | Week 4 | |
|---|---|---|---|---|---|
| Positive mood (0 = not true at all, 7 = very true)* | |||||
| 4.1±1.2 | 4.4‡±1.1 | 4.6‡±1.2 | 4.7‡±1.1 | 4.7‡±1.1 | |
| Negative mood (0 = not true at all, 7 = very true) † | |||||
| 2.3±1.2 | 1.9‡±1.2 | 1.8‡±1.2 | 1.8‡±1.2 | 1.7‡±1.2 |
Alert, full of pep/energetic, friendly, and well/good.
Angry, irritable, sad or blue, tired, nervous.
P <.0001 versus baseline
Figure 3.
Positive and negative mood scores.
Discussion
In the aging male population, serum testosterone levels begin decreasing over time so that approximately 20% of men over the age of 50 years become hypogondal; this rate increases to 49% of men after the age of 80 years.7 Two of the symptoms associated with low testosterone levels are reduced sexual function and low libido. Because earlier clinical trials showed that testosterone supplementation in hypogonadal men improves sexual function and sexual desire within 30 days of treatment, it would be useful to the clinician to know how quickly to expect to see a response in sexual function. START accomplished this by collecting information on sexual activity and mood on a daily basis for 1 week before initiation of Testim and then daily for 30 days of Testim therapy.
Sexual desire and nighttime erections increased, showing a significant increase within the first week of Testim therapy that was maximized by 2 weeks of therapy and then maintained for the 2 additional weeks through the end of the study. On the other hand, frequency of intercourse began to show a significant increase after 2 weeks of Testim therapy, even though sexual enjoyment with a partner and satisfaction with duration of erections showed significant increases after the first week of therapy. By the end of the 30-day treatment period, 39% of the patients reported more days of intercourse during the last week compared with the baseline week. During the same time period, indicators of positive mood showed an increase over time whereas indicators for negative mood showed an improvement over time. Patients who supplied data for at least 25 days during treatment reported having intercourse an average of 4 days during the month, or roughly once a week. During the week prior to treatment, patients on average had intercourse less than once per week (0.7 d/wk). Because START did not require any specific level of sexual activity, it is not possible to compare it with other studies, such as erectile dysfunction studies, which did require a minimal level of attempts at sexual activity.
The data suggest that improvements will be seen within 2 weeks of therapy. If improvements are not noted by then, it may be necessary to check serum testosterone levels to determine whether the dose is sufficient to normalize the patient’s testosterone levels to the eugonadal range. There is also a suggestion that increases in sexual desire may lead to increases in frequency of intercourse. This may be important to men who have both erectile dysfunction and low serum testosterone levels, because current erectile dysfunction treatments do not have an impact on sexual desire.
Main Points.
Significant sexual function improvement (desire, motivation, spontaneous erection, performance, enjoyment, and duration of erection) was seen by week 1, continued to improve through week 2, and was then maintained to week 4.
Significant mood indicators showed improvement by week 1, continued to improve through week 2, and were then maintained to week 4.
Footnotes
This study was supported by a grant from Auxilium Pharmaceuticals, Inc., Norristown, PA.
References
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