The efficacy and safety of short-acting testosterone ointment (Glowmin) for late-onset hypogonadism in accordance with testosterone circadian rhythm

Abstract

Introduction: It is well known that there is a reduction of circadian rhythm in blood testosterone levels with aging. Our previous report revealed that 3 mg of short-acting testosterone ointment (Glowmin: GL) elevated serum testosterone levels to within the physiological range for 4–6 h. The aim of this study was to clarify the clinical efficacy and safety of GL used topically once every morning, to enhance the circadian rhythm of testosterone, for late-onset hypogonadism (LOH).

Methods: A total of 61 LOH patients received 3 mg of GL topically once a day in the morning on scrotal skin for 24 weeks. The clinical efficacy of GL was evaluated by the aging males symptoms (AMS) scale, and blood sampling tests were measured before and after GL treatment.

Results: Mean patients age was 55.3 ± 9.2 years old. Total AMS scores at 4, 12, and 24 weeks after GL treatments significantly decreased. The results of sub-analysis of AMS, including psychological, physical, and sexual factors also significantly improved after GL treatments. No severe adverse reactions or abnormal laboratory data were reported.

Conclusions: This study shows that TRT for LOH with once daily GL treatment supports testosterone circadian rhythm and should be considered to be an effective and safe therapy for LOH.

Keywords:

• Late-onset hypogonadism
• testosterone replacement therapy
• short-acting testosterone ointment
• testosterone circadian rhythm
• aging male symptoms score

Introduction

Testosterone replacement therapy (TRT) has been previously reported for the treatment of late-onset hypogonadism (LOH) [1]. This report revealed that 3 mg of a short-acting testosterone ointment (Glowmin: GL) elevated serum testosterone levels within the physiological range for 4–6 h, and administration of 3 mg GL twice daily alleviated various symptoms of LOH patients.

It has also been reported that there is a reduction of circadian rhythm in blood testosterone levels with aging [2], so it can be reasoned that circadian rhythm may be important for anti-aging and treatment of LOH. When a short-acting testosterone ointment (GL) is administered early (between 6:00 and 8:00 am) in the morning; it might have the potential to enhance the circadian rhythm of physiological testosterone levels.

Aim

The aim of this study was to assess the clinical efficacy and safety of testosterone ointment (GL) administration in LOH patients once every morning, which may enhance the circadian rhythm of testosterone.

Methods

A total of 61 men who attended our outpatient clinic for evaluation of LOH between April 2011 and March 2015 were assessed. At their first visit, they were evaluated by medical history, physical examination, clinical parameters, and questionnaires prior to any treatment for LOH. The patients in this study had previously never been administered any LOH medications, such as testosterone replacement therapy. The Institutional Review Board (IRB) had approved this prospective clinical study; and informed consents were obtained from all participants.

These 61 LOH patients received 3 mg of GL once daily between 6:00 and 8:00 am on their scrotal skin and the clinical efficacy of GL was estimated by the aging males’ symptoms scale (AMS) assessed at baseline, 4, 12, and 24 weeks after administration. Blood screening including total testosterone (TT), free testosterone (FT), luteinizing hormone (LH), follicle stimulating hormone (FSH), hemoglobin, aspartate transaminase (AST), alanine transaminase (ALT), creatinine, cholesterol, triglyceride, blood sugar, and prostate-specific antigen (PSA) were measured at baseline, 12 weeks (at 1 h after GL application) and 24 weeks (just before GL application) after treatment.

Main outcome measures

The efficacy and safety of once-daily administration of GL were investigated by evaluating the AMS scale and the other clinical data. The data was analyzed using Stat View for Windows version 5.0 (SAS Institute Inc. Cary, NC), assuming p < .05 as significant.

Results

Patients ages ranged from 40 to 81 years (mean 55.3 ± 9.2). Their health status is described in Table 1. Their body mass index (BMI) was 24.2 ± 1.9. Of 61 subjects, six had diabetes mellitus (DM), eight had cardiovascular disease, and 38 suffered from psychological disorders. As there is not a lot of obesity in Japan only few patients had DM and/or cardiovascular diseases. However, many patients exhibited psychological disorders. It is one of the unique and significant characteristics of Japanese LOH patients that psychological problems, especially depression, are bothersome issues. Total AMS scores before treatment were from 29 to 74 (mean 51.3 ± 9.8). Total AMS scores at 4, 12, and 24 weeks after GL treatments significantly decreased to 42.7 ± 11.6, 40.7 ± 11.2, and 38.8 ± 8.8, respectively (Figure 1). The results of sub-analysis of AMS, including psychological, physical, and sexual factors also significantly improved after GL treatments (Figures 2–4).

Figure 1. Change of aging male symptom (AMS) scores pretreatment, 4, 12, and 24 weeks after daily 3 mg of a short-acting testosterone ointment (Glowmin: GL) administration. Score of total AMS significantly decreased after GL treatment.

Figure 2. Change of AMS sub-scores (psychological factors) pretreatment, 4, 12, and 24 weeks after daily 3 mg of GL administration. Score of psychological factors significantly decreased after GL treatment.

Figure 3. Change of AMS sub-scores (physiological factors) pretreatment, 4, 12, and 24 weeks after daily 3 mg of GL administration. Score of physiological factors significantly decreased after GL treatment.

Figure 4. Change of AMS sub-scores (sexual factors) pretreatment, 4, 12, and 24 weeks after daily 3 mg of GL administration. Score of sexual factors significantly decreased after GL treatment.

Table 1. The patients’ baseline health status, including body mass index (BMI), diabetes mellitus (DM), cardiovascular disease, and psychological disorders.

BMI (n = 55)	DM	Cardiovascular diseases	Psychological disorders
Range: 19.9∼28.1	Yes, on medical treatments: 3	Yes, on medical treatments: ８	Yes, on medical treatments: 34
Mean ± SD: 24.2 ± 1.9	Yes, on diet therapy: 3	(Hypertension, Arrhythmias, etc.)	Yes, observation: ４ (Depression, Sleep disturbance, etc.)
(BMI unknown: n=6)	No: 55	No: 53	No: 23

Blood screening revealed that total and FT levels were significantly elevated 1 h after GL administration to within the physiological range. In addition, nadir serum total and FT levels prior to GL application were consistently maintained at 24 weeks after GL treatments compared with their baseline hormonal levels (Table 2).

Table 2. Serum total and free testosterone levels before treatment and after daily 3 mg of GL administration at 12 and 24 weeks.

	Before GL treatment	1 h after GL application (at 12 weeks)	Before GL application (at 24 weeks)
TT (ng/mL)	3.77 ± 1.33	4.80 ± 1.95*	4.45 ± 1.93
FT (pg/mL)	6.3 ± 2.2	8.7 ± 3.8*	7.7 ± 3.4

Total and free testosterone levels were significantly elevated 1 h after GL administration in physiological range at 12 weeks. In addition, nadir serum total and free testosterone levels prior to GL application were maintained at 24 weeks compared with baseline hormonal levels.

*p = < .01 (before treatment vs. 1 h after application).

Other blood tests revealed no significant difference compared with the baseline results. No severe adverse reactions or abnormal laboratory data were reported (Table 3).

Table 3. Blood screening after GL treatment revealed no significant difference compared with baseline results.

	Before	12 Weeks after	24 Weeks after
LH (mIU/mL)	3.49 ± 2.39	3.19 ± 1.82	3.51 ± 2.57	NS
FSH (mIU/mL)	6.64 ± 7.74	6.65 ± 6.75	6.91 ± 7.26	NS
Hemoglobin (g/dL)	15.2 ± 1.0	15.3 ± 0.9	15.4 ± 0.8	NS
AST (IU/L)	23.1 ± 8.4	24.2 ± 6.5	24.1 ± 5.8	NS
ALT (IU/L)	25.3 ± 12.8	25.6 ± 13.7	25.9 ± 11.2	NS
Creatinine (mg/dL)	0.88 ± 0.12	0.91 ± 0.17	0.91 ± 0.12	NS
Cholesterol (mg/dL)	192.1 ± 26.4	188.8 ± 26.4	199.2 ± 23.5	NS
TG (mg/dL)	173.0 ± 107.9	184.7 ± 167.2	173.9 ± 99.4	NS
Blood sugar (mg/dL)	114.8 ± 29.9	112.6 ± 39.0	103.3 ± 19.7	NS
PSA (ng/mL)	0.85 ± 0.62	0.92 ± 0.79	0.89 ± 0.74	NS

LH: luteinizing hormone; FSH: follicle-stimulating hormone; AST: aspartate transaminase; ALT: alanine transaminase; TG: triglyceride; PSA: prostate specific antigen; NS: not significant.

Discussion

The aging male endures several symptoms, including physiological, psychological, and sexually related that are identified as LOH symptoms [3,4]. Some of these symptoms in LOH patients are related to a decline in testosterone levels. LOH treatment is used to increase the supply of testosterone which has decreased due to aging. There are several suitable forms of TRT, such as oral (Testosterone undecanoate), intra-muscle injections (Testosterone undecanoate and Testosterone enanthate), trans-dermal (Testosterone patch and Testosterone gel), buccal (Testosterone buccal), and testosterone crystallization (Testopel, Malvern, PA) [5,6]. However, only intra-muscle injection (Testosterone enanthate) and testosterone ointment (natural type testosterone and Glowmin; GL) are clinically available in Japan for LOH patients [7]. GL is a short-acting testosterone ointment which elevates the serum testosterone level to within the physiological range for 4–6 h [1]. GL treatment is recommended to be applied twice daily to the scrotal skin. In this study, we sought to show that once-daily administration was effective and as a by-product this would also reduce the patient’s cost and time.

We applied GL to scrotal skin. Scrotal skin is thin and has high steroid permeability. Pharmacokinetics of serum testosterone levels after scrotal skin application seems to depend on testosterone forms. The scrotal application of hydroalcoholic 2.5% testosterone gel (TGW) is as effective and safe as the 2.5 mg Androderm^® patches, whereas non-scrotal dermal application of TGW is superior to the patch and scrotal application [8]. Testosterone cream administration to scrotal skin is well tolerated and produces dose-dependent peak serum testosterone concentration with a much lower dose relative to the non-scrotal transdermal route [9]. Absorption of GL has been reported from various different sites, and the results indicated the sites of relatively high absorptions of testosterone were the jaw angle region after shaving, scrotal, and jaw angle region before shaving [10]. Thus, we administered GL onto the scrotal skin.

TRT for LOH is an effective treatment, and TRT should maintain not only physiological levels of serum testosterone levels as well as the metabolites of testosterone including estradiol which optimizes maintenance of bone, muscle mass, libido, virilization, and sexual function [11]. It is the very significant to consider testosterone physiological circadian rhythms. There are some new testosterone formulations that keep the serum testosterone levels in the physiological range imitating its circadian rhythm [12]. However, contemporary TRTs are prescribed with little considerations for circadian rhythm of testosterone. The loss of circadian rhythm of testosterone has been reported as one of the most important phenomena in the aging male [2]. Although the role of testosterone circadian rhythm is unclear, TRT being homogeneous with testosterone circadian rhythm for LOH seems to be physiological and significant. Most of the testosterone replacement medications do not address the short-acting profile of serum testosterone levels; hence they are not suitable for TRT in relation to testosterone circadian rhythms. We considered that a daily application of 3 mg GL in the morning may have the efficacy to improve LOH symptoms along with physiological testosterone circadian rhythm.

TRT should lead to serum testosterone levels in the medium–normal range as reported for healthy young males [12]. However, it has been recommended that older males need higher levels of testosterone from administration of TRT than younger hypogonadal patients to reach any significant benefit [13]. We were initially unsure whether the IRB approved dose of testosterone (3 mg/d) may be too small, and only limited efficacy may be obtained. However, according to this study, low dose GL treatment promoting testosterone circadian rhythm is considered to be an effective and safe therapy. Furthermore, our sub-analysis revealed that there was no significant difference of total AMS score at pre-TRT, 4, and 12 W after GL TRT between 33 younger (≦55 years-old) and 28 older (>55 years-old) patients.

TRT is effective not only for LOH and its comorbidities [1,14], but also for male LUTS [15,16]. To maintain efficacy of TRT for LOH and male LUTS, continuous administration of TRT is important. We believe low dose once daily administration of GL is applicable for improvement of LOH symptoms and can also be rationalized as more cost-effective. In addition, with the smaller dose of testosterone less side effects are expected.

The relationship between TRT and prostate cancer incidence is another concern for LOH patients. The incidence of prostate cancer with TRT has been studied in several publications [17–19]. It has been reported that men with a lower baseline testosterone level (<250 ng/dL) will experience a rise in PSA with TRT [20]. Findings in the previous reports are heterogeneous. It seems that at least PSA should be measured routinely to monitor prostate cancer incidence in any clinical study using TRT. Naturally, continuous clinical follow-up for serum PSA levels is required. However, during this study, there were no PSA elevations nor were any patients diagnosed with prostate cancer.

Long-term TRT using testosterone undecanoate injection has also been reported to relieve several elements of metabolic syndrome, including BMI, blood pressure, and fasting glucose [21,22]. A large observational cohort study revealed normalization of testosterone level after TRT was associated with a significant reduction in all-cause mortality, myocardial infarction, and stroke [23]. Thus, it is considered that long-term TRT contributes significantly to men’s health. However, in Japan, only testosterone enanthate injection and trans-dermal GL ointment are clinically used as TRT for LOH patients [7]. Once daily GL treatment which promotes testosterone circadian rhythm is considered to be treatment strategy for LOH. On the other hands, once daily GL treatment might be an undertreatment for conditions, such as metabolic syndrome, all-cause mortality, myocardial infarction, and stroke. Only a few of our LOH patients suffered from metabolic syndrome, and GL treatments were effective to relieve their symptoms.

In a previous study, we noted a decrease of LH was observed after twice daily GL application [1]. However, this once-daily GL treatment did not decrease FSH and LH. This data indicates low dose TRT with once-daily GL may be a possible application for LOH patients who are seeking treatment for male fertility. This could also be another benefit of this application.

Daily 5 mg phosphodiesterase (PDE) 5 inhibitor (Tadalafil) has been recently reported to improve endothelial function in benign prostatic hyperplasia patients [24,25]. Improvement of endothelial function can reduce arterial sclerosis which can result in prevention of metabolic syndrome [26,27]. TRT also improves several metabolic syndrome symptoms in hypogonadal men [28–30]. Accordingly, both PDE 5 inhibitors and testosterone are significant medications to improve LOH and metabolic syndrome, and hence results in contributing to men’s health and well-being. This current report is a short observational study and is limited in terms of long-term efficacy and safety and as such further investigation is required. However, our data suggested that a daily GL treatment which promotes testosterone circadian rhythm might be useful therapy for LOH.

Conclusion

Decrease of testosterone due to circadian rhythm is an important issue in the aging male. Although the role of testosterone circadian rhythm is unclear the addition of TRT for LOH reduces the physiological oscillation of testosterone circadian rhythm. Our data has also shown that once daily low dose GL treatment is safe and effective for LOH patients.

Disclosure statement

No potential conflict of interest was reported by the authors.