Form Of Testosterone Replacement Therapy Research Articles

(070) Testosterone Therapy in Men with Klinefelter Syndrome: Analysis of a Global Federated Research Network

Abstract Introduction Klinefelter syndrome (KS) is a genetic condition in which a male is born with an extra X-chromosome and is one of the on-label indications for testosterone replacement therapy (TRT). The prevalence of testosterone deficiency in men with KS is difficult to predict and not well described in the literature. Furthermore, there is no previous literature detailing the rates of TRT prescription in men diagnosed with KS. Objective We aimed to determine the rates of hypogonadism and prescription of TRT in men with KS using a large, federated research database. We hypothesized that men with KS are undertreated for testosterone deficiency with TRT due to a combination of factors including a poor understanding of hypogonadism in this population and neurocognitive issues leading to delay in seeking treatment for hypogonadism. Methods We queried TriNetX, a large, multicenter electronic health record database, to identify all men with a diagnosis of Klinefelter syndrome (ICD-10-CM Q98.4) excluding men with prescription of TRT prior to diagnosis of KS or a diagnosis of KS more than 20 years ago. Descriptive analysis on associated comorbidities and demographic characteristics was performed. We then filtered the initial cohort to find men who received a laboratory measurement of testosterone level on the day of diagnosis with KS or later. Prevalence of testosterone deficiency was determined as defined by testosterone level < 300 ng/dl. The primary outcome of the study was prescription of any of the following forms of TRT on the day of diagnosis or later using associated medication codes: testosterone, testosterone 17-phenylpropionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate. Rates of TRT prescription were determined for both the initial cohort and the hypogonadal subgroup. Results There were 5,437 total men with diagnosis of KS. A total of 1,581 men with KS received laboratory measurement of testosterone level, 1,113 (70.4%) of whom were hypogonadal. Mean testosterone level in this group was 354 ng/dL [50 – 658]. Of the 1,113 men found to be hypogonadal, only 657 (59.0%) men were given prescription for TRT. Conclusions This is the first study to evaluate TRT prescribing habits in men with KS. In this large, retrospective study, TRT was under-prescribed in men with KS. Further studies are needed to corroborate these findings and to evaluate the barriers to receiving care in this population. Disclosure No

The behavioral profile of 49,XXXXY and the potential impact of testosterone replacement therapy

Purpose49,XXXXY (1:85,000-100,000) is a rare sex chromosome aneuploidy that often presents with complex musculoskeletal abnormalities, decreased cognitive capabilities, speech and language dysfunction, and behavioral complications. Hormonal replacement therapy, or testosterone replacement therapy, is associated with improved neurodevelopmental and behavioral outcomes in males with 49,XXXXY. Two forms of testosterone replacement therapy, early hormonal treatment (EHT) and hormonal booster therapy (HBT), are associated with improved neurodevelopmental and behavioral outcomes in these boys. This study investigates the impact of EHT and HBT on behavioral symptoms in males with 49,XXXXY. MethodsA total of 59 individuals were divided into 4 groups: 19 no testosterone (no-T), 23 EHT, 6 HBT, and 11 EHT and HBT. An analysis of variance examined group differences on the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function ranging from 5 to 18 years. ResultsAlthough no differences were identified on the Behavior Rating Inventory of Executive Function, the 3 hormonal replacement therapy groups presented with decreased complications on numerous variables on the Child Behavior Checklist; these include somatic complaints (P = .0095), somatic problems (P = .041), internalizing problems (P = .034), externalizing problems (P = .0001), and withdrawn/depression (P = .025). ConclusionThis study presents evidence that HBT may be a beneficial treatment for individuals with 49,XXXXY.

Testosterone Therapy in Men with Klinefelter Syndrome: Analysis of a Global Federated Research Network.

The objective of this study was to determine the rates of hypogonadism and prescription of testosterone replacement therapy (TRT) in men with Klinefelter syndrome (KS). We hypothesized that men with KS are under-treated for testosterone deficiency with TRT due to a combination of factors, including a poor understanding of hypogonadism in this population and neurocognitive issues leading to delay in seeking of treatment for hypogonadism. We queried TriNetX, a large multicenter electronic health record database, to identify all men with a diagnosis of KS (ICD-10-CM Q98.4). Prevalence of testosterone deficiency was determined as defined by testosterone level < 300 ng/dL. The primary outcome of the study was prescription of any of the following forms of TRT on the day of diagnosis or later. There were in total 5437 men with diagnosis of KS. A total of 1581 men with KS received laboratory measurement of testosterone level, 1113 (70.4%) of whom were hypogonadal. Mean testosterone level in this group was 354 ng/dL [50-658]. Of the 1113 men found to be hypogonadal, only 657 (59.0%) men were given prescription for TRT. This is the first study to evaluate TRT prescribing habits in men with KS. In this large retrospective study, TRT was underprescribed in men with KS. Further studies are needed to corroborate these findings and to evaluate barriers to receiving care in this population.

Direct conversion from long-acting testosterone replacement therapy to Natesto allows for spermatogenesis resumption: Proof of concept.

Long‐acting testosterone replacement therapy (TRT) suppresses spermatogenesis. A short‐acting TRT, Natesto, maintains spermatogenesis in some men. This study evaluated hormonal and semen parameters converting men from long‐acting TRT to Natesto. Baseline hormones, again on long‐acting TRT and 1 month after converting to Natesto, as well as semen parameters 3 months after converting to Natesto were assessed. Twenty‐seven men were directly converted from long‐acting forms of TRT to Natesto. Mean duration on long‐acting TRT was 24.3 ± 19 months. Testosterone levels were similar on long‐acting forms of TRT and Natesto, however; E2 levels were significantly lower on Natesto. Ten men had semen analyses demonstrating azoospermia while on long‐acting TRT, the remainder were presumed to be azoospermic or severely oligospermic which has been well established as an effect of long‐acting TRT. All 27 men had resumption of spermatogenesis with a mean sperm concentration of 50.7 million/ml after converting to Natesto, considered within the fertile range. One couple achieved a pregnancy 4 months after converting to Natesto. Hypogonadal men on long‐acting TRT interested in resumption of spermatogenesis may convert directly to Natesto for an opportunity to do so while remaining on a form of TRT and achieving lower E2 levels.

Changes in anthropometric characteristics, androgen and estrogen levels during correction of male hypogonadism with testosterone or hCG: results of a retrospective comparative study

Background: The use of testosterone replacement therapy (TRT) is widespread. Despite the positive changes, such as: an increase in testosterone levels, an improvement in erectile function and an increase in libido, it is possible to develop a negative manifestation — hyperestrogenism. To date, there are no studies assessing the prevalence of hyperestrogenism in the presence of TRT.Aim: To study the reliability of an increase in total testosterone and estradiol levels and changes in total weight, body mass index (BMI), waist circumference (WC) and hips (OB), depending on the type of TRT and hCG therapy.Materials and methods: For retrospective analysis, the medical records of patients with baseline testosterone deficiency and normal estradiol levels, who were prescribed TRT or hCG therapy, were selected. The patients were divided into 3 groups depending on the form of TRT and hCG therapy. The level of testosterone, estradiol, sex hormone binding globulin (SHBG), weight, OT, OB, BMI in each group was assessed 2 times — before the appointment of treatment and at different periods of treatment, for example, after 3–6–9 and 12 months. Most of the patients had a period of monitoring these parameters before the appointment of TRT or hCG therapy and after 6 months.Results: The increase in the levels of total testosterone and estradiol against the background of TRT in the total sample was 109.6% and 111.3%, respectively. In each group, increases in total testosterone and estradiol levels were significant, p ≤ 0.001. The level of total testosterone to physiological values increased only in the 2-nd group — reaching the average-normal, recommended levels, from 8.7 ± 0.5 (2.5) to 16 ± 2 (10). The maximum rises in total testosterone, as well as estradiol, were noted in the 1st group, from 9.5 ± 0.72 nmol / L (3) to 24.9 ± 2.7 nmol / L (11.62)) and with 24.19 ± 2 (8.5) to 58.1 ± 4 (18.1), respectively. TRT, like hCG therapy, promotes an increase in the level of estradiol, which was demonstrated in all groups, and not only in group 1-st: in group 2-nd from 28.1 ± 2.3 (11.3) to 55 ± 4 (20) and in the 3-rd group from 27.1 ± 2.5 (10.5) to 55.8 ± 4.6 (19.6). On average for the entire sample, from 26.6 ± 1.32 (10.2) to 56.2 ± 2.5 (19). Weight loss on TRT was significant only in the 2-nd group, and in all parameters — weight, BMI, waist and hip circumference. In the 3-rd group, BMI, WC and OB values also slightly decreased. In the 1-st group, the total weight slightly increased, while the BMI did not change, as did the OB value, and the OT value decreased slightly.Conclusion: TRT significantly increases the levels of total testosterone and estradiol, contributing to the normalization of testosterone levels, as in the 2-nd group, or the development of supraphysiological levels of total testosterone and hyperestrogenism, as in the 1st and 3-rd groups. Given that there is a strong belief that TRT leads to significant weight loss, our study confirmed this statement only in the 2-nd group.

Изменения антропометрических характеристик, уровня андрогенов и эстрогенов при коррекции мужского гипогонадизма препаратами тестостерона или хорионического гонадотропина: результаты ретроспективного сравнительного исследования

Background: The use of testosterone replacement therapy (TRT) is widespread. Despite the positive changes, such as: an increase in testosterone levels, an improvement in erectile function and an increase in libido, it is possible to develop a negative manifestation — hyperestrogenism. To date, there are no studies assessing the prevalence of hyperestrogenism in the presence of TRT. Aim: To study the reliability of an increase in total testosterone and estradiol levels and changes in total weight, body mass index (BMI), waist circumference (WC) and hips (OB), depending on the type of TRT and hCG therapy. Materials and methods: For retrospective analysis, the medical records of patients with baseline testosterone deficiency and normal estradiol levels, who were prescribed TRT or hCG therapy, were selected. The patients were divided into 3 groups depending on the form of TRT and hCG therapy. The level of testosterone, estradiol, sex hormone binding globulin (SHBG), weight, OT, OB, BMI in each group was assessed 2 times — before the appointment of treatment and at different periods of treatment, for example, after 3–6–9 and 12 months. Most of the patients had a period of monitoring these parameters before the appointment of TRT or hCG therapy and after 6 months. Results: The increase in the levels of total testosterone and estradiol against the background of TRT in the total sample was 109.6% and 111.3%, respectively. In each group, increases in total testosterone and estradiol levels were significant, p ≤ 0.001. The level of total testosterone to physiological values increased only in the 2-nd group — reaching the average-normal, recommended levels, from 8.7 ± 0.5 (2.5) to 16 ± 2 (10). The maximum rises in total testosterone, as well as estradiol, were noted in the 1st group, from 9.5 ± 0.72 nmol / L (3) to 24.9 ± 2.7 nmol / L (11.62)) and with 24.19 ± 2 (8.5) to 58.1 ± 4 (18.1), respectively. TRT, like hCG therapy, promotes an increase in the level of estradiol, which was demonstrated in all groups, and not only in group 1-st: in group 2-nd from 28.1 ± 2.3 (11.3) to 55 ± 4 (20) and in the 3-rd group from 27.1 ± 2.5 (10.5) to 55.8 ± 4.6 (19.6). On average for the entire sample, from 26.6 ± 1.32 (10.2) to 56.2 ± 2.5 (19). Weight loss on TRT was significant only in the 2-nd group, and in all parameters — weight, BMI, waist and hip circumference. In the 3-rd group, BMI, WC and OB values also slightly decreased. In the 1-st group, the total weight slightly increased, while the BMI did not change, as did the OB value, and the OT value decreased slightly. Conclusion: TRT significantly increases the levels of total testosterone and estradiol, contributing to the normalization of testosterone levels, as in the 2-nd group, or the development of supraphysiological levels of total testosterone and hyperestrogenism, as in the 1st and 3-rd groups. Given that there is a strong belief that TRT leads to significant weight loss, our study confirmed this statement only in the 2-nd group.

Chronic Testosterone Deprivation Sensitizes the Middle-Aged Rat Brain to Damaging Effects of Testosterone Replacement

Introduction: An increasing number of middle-aged men are being screened for low testosterone levels and the number of prescriptions for various forms of testosterone replacement therapy (TRT) has increased dramatically over the last 10 years. However, the safety of TRT has come into question with some studies suggesting increased morbidity and mortality. Objective: Because the benefits of estrogen replacement in postmenopausal women and ovariectomized rodents are lost if there is an extended delay between estrogen loss and replacement, we hypothesized that TRT may also be sensitive to delayed replacement. Methods: We compared the effects of testosterone replacement after short-term (2 weeks) and long-term testosterone deprivation (LTTD; 10 weeks) in middle-aged male rats on cerebral ischemia, oxidative stress, and cognitive function. We hypothesized that LTTD would increase oxidative stress levels and abrogate the beneficial effects of TRT. Results: Hypogonadism itself and TRT after short-term castration did not affect stroke outcome compared to intact rats. However, after long-term hypogonadism in middle-aged male Fischer 344 rats, TRT exacerbated the detrimental behavioral effects of experimental focal cerebral ischemia, whereas this detrimental effect was prevented by administration of the free-radical scavenger tempol, suggesting that TRT exacerbates oxidative stress. In contrast, TRT improved cognitive performance in non-stroked rats regardless of the length of hypogonadism. In the Morris water maze, peripheral oxidative stress was highly associated with decreased cognitive ability. Conclusions: Taken together, these data suggest that TRT after long-term hypogonadism can exacerbate functional recovery after focal cerebral ischemia, but in the absence of injury can enhance cognition. Both of these effects are modulated by oxidative stress levels.

Reproductive endocrinology: Are intramuscular testosterone injections harmful?

Injectable testosterone esters and transdermal testosterone gels have generally been assumed to be equally safe and effective forms of testosterone-replacement therapy for male hypogonadism. Now, findings from a recent study suggest that transdermal testosterone gels are superior to injectable testosterone esters in terms of reducing cardiovascular events, all-cause hospitalizations and all-cause mortality.

Retrospective Investigation of Testosterone Undecanoate Depot for the Long-term Treatment of Male Hypogonadism in Clinical Practice

Testosterone undecanoate depot (TUD) administered intramuscularly is an effective form of testosterone replacement therapy (TRT) for male hypogonadism. Because of the ease of administration, TUD therapy may be preferable to subcutaneously implanted extended release T pellet implants (TI). The primary objective was to retrospectively assess the efficacy and safety of long-term (≥ 2 years therapy) TUD therapy in the clinical setting. The secondary objective was to retrospectively compare TUD with TI therapy. Retrospective data were collected from the Waikato Hospital Endocrine Database for 179 hypogonadal men treated with TUD for ≥ 2 years from 1998-2011, with 124 of these men receiving previous TI therapy. The main outcome measure for efficacy was serum trough total testosterone (TT), and for safety an increase in hemoglobin (Hb) and/or hematocrit (Hct), rise in prostate-specific antigen (PSA) and/or prostatic biopsy and alteration in body mass index and lipid profile. Additional outcome measures were changes in the dosing and/or interval regimens for TUD therapy. Overall, 72% of trough TT levels were in the normal range for TUD therapy compared with 53% of trough TT levels during TI therapy. TUD therapy was well tolerated with 162 men (90.5%) completing 2 years of treatment, and only seven men (3.9%) stopping TUD because of adverse effects. A rise in Hb and/or Hct occurred in 25 men (14%), and a significant rise in PSA in 20 men (13%) at some stage during TUD therapy. At 2 years, 91% of men received the standard 1,000 mg TUD dose with 66% at the standard dosing interval of 10-14 weekly. TUD is an efficacious, safe, and well tolerated form of TRT, and individual optimisation of the dose and/or interval is only required in the minority of men. Particularly given the ease of administration, TUD was the preferred TRT for both patients and clinicians.

12-Month Observation of Testosterone Replacement Effectiveness in a General Population of Men

Background: Testosterone decline becomes more prevalent as men age and symptomatic testosterone deficiency is associated with potentially serious comorbidities. Despite limitations, registries can provide an opportunity to accumulate data regarding disease management in a typical patient population, including diagnosis, treatment, and outcomes. Materials and Methods: The Testim Registry in the United States (TRiUS) was a prospective, 12-month, observational cohort registry of men prescribed Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.) for the first time; patients previously on other forms of testosterone replacement therapy (TRT) were eligible to participate in the study as well. The registry recorded total testosterone (TT) and free testosterone (FT) levels, prostate-specific antigen (PSA), sexual function, mood/depression, and cardiometabolic and anthropometric criteria before and after TRT. Changes over time were analyzed by analysis of variance, and linear regression and Pearson product-moment correlation coefficients were used to examine relationships between variables. Results: At baseline, 849 patients from 72 sites were enrolled, with 743 of 849 started on 5 g gel/day (50 mg testosterone/day) and 106 of 849 started on 10 g gel/day (100 mg testosterone/day). Mean TT and FT levels increased significantly after 3 months of TRT (TT level, 16.8 ± 9.87 nmol/L [485 ± 284 ng/dL], P < 0.001; FT level, 286.3 ± 224.9 pmol/L [82.5 ± 64.8 pg/mL], P < 0.001) and were maintained at eugonadal levels. Mean PSA levels increased significantly (P = 0.004) from 1.12 ± 1.11 μg/L (1.12+1.11 ng/mL) at baseline to 1.26 ± 1.22 μg/L (1.26 ± 1.22 ng/mL) after 12 months of TRT, although changes were well within guidelines (< 1.4 μg/L/year increase). Significant improvements were seen in sexual function and mood/depression at 3 months and in metabolic parameters at 12 months. Conclusion: Testosterone deficiency symptoms improved with TRT use in men; sexual function and mood/depression improvements were seen before metabolic improvements. Prostate-specific antigen levels increased, although increases were within guideline-determined safety limits.

PIH79 Medication Adherence and Persistence for Hypogondal Patients Treated with Topical Testosterone Therapy: A Retrospective Claims Analysis

The diagnosis of hypogonadism is established in symptomatic men with consistently low levels of serum testosterone, whether due to specific diagnoses, such as Klinefelter syndrome, or non-specific diagnoses, which often occur with aging. Testosterone gels are the most common form of testosterone replacement therapy for hypogonadism in the United States, but little is known about patient adherence and persistence with therapy. This study seeks to examine testosterone gel adherence and persistence among hypogonadism patients. The type of hypogonadism (specific versus non-specific) was classified using either ICD-9-CM diagnostic codes or testosterone prescription codes in the Thomson Reuters MarketScan® Database in 2009. Medication persistence was defined as the length of therapy (LOT) from the index date to the earliest ending date of the last prescription, defined as either the date of the first gap of >30 days between prescriptions or the end of study period (12 months). Medication adherence was measured by medication possession ratio (MPR) in the 6 months follow-up period. Adherence rate was defined as percent of MPR ≥0.8. LOT, MPR and adherence rate were calculated by diagnostic code and age group and compared using t-test or chi-square test. 91,200 men met study criteria for hypogonadism: 11.1% with specific and 89.9% with non-specific diagnostic codes. The mean LOT was 196 days and 178 days, respectively (p< 0.0001). MPR and adherence rates were similar between men with specific (0.4 and 8.6%, respectively) and non-specific (0.4 and 9.0%, respectively) diagnoses. LOT, MPR and adherence rate were numerically similar across all age groups. Unexpectedly, diagnostic specificity and age were not found to be key etiologic factors in testosterone gel adherence and persistence for hypogonadal men. Unexplored factors that might provide more sensitivity include other testosterone application methods, hypogonadal symptom severity, and ascertainment of testosterone levels.

The long‐term efficacy and safety of a testosterone mucoadhesive buccal tablet in testosterone‐deficient men

What's known on the subject? and What does the study add? Striant® SR is the only available buccal delivery system for testosterone replacement therapy. Previous pharmacokinetic studies have shown that Striant SR effectively produces physiological serum testosterone levels in hypogonadal men. Efficacy and safety data from previously unpublished studies over 2 years of continuous use indicate that Striant SR is effective long term in maintaining serum testosterone within a physiological range, is well tolerated and has a high level of patient acceptance. Striant® sustained-release (SR) is a mucoadhesive buccal tablet (30 mg testosterone, The Urology Company) that adheres to the gum surface in the mouth providing controlled- and sustained-release of testosterone over a 12-h dosing period, offering a unique and rational method of testosterone delivery. Striant SR is indicated for testosterone-replacement therapy (TRT) for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. Pharmacokinetic studies have shown that testosterone is released from Striant SR in a manner similar to the normal daily rhythm of endogenous testosterone secretion, with serum levels rising rapidly after insertion and peak levels reached by the second 12-hourly dose with no accumulation over time. In clinical trials involving hypogonadal men receiving Striant SR for up to 2 years, mean serum testosterone levels have always remained within the normal range. Striant SR is well tolerated, with gum-related disorders (such as irritation, inflammation and gingivitis) and taste perversion being the most commonly reported adverse events, reported by 5.6-16.3% and 3.0-4.1% of patients, respectively. Once patients have become accustomed to it, Striant SR has a high level of patient acceptance. In a long-term study, 90% of patients rated the twice-daily dosing as acceptable, just under half preferred it to other forms of TRT that they have used and 96% found it to be cosmetically acceptable. There is no clinically significant risk of testosterone transfer from Striant SR, as any testosterone that may be present in the saliva when swallowed is subject to extensive first-pass hepatic metabolism. It is pertinent to note that the saliva of eugonadal men contains similar levels of endogenous testosterone. Buccal delivery is particularly suitable where easy and rapid reversal of treatment might be required (such as in late-onset hypogonadism) and where there is a need to avoid the potential for transfer of testosterone to women and young children.

Men's Health, Low Testosterone, and Diabetes Individualized

Testosterone plays a critical role in male reproductive and metabolic functioning. Serum testosterone levels decrease with age, and low testosterone is associated with a variety of comorbidities, including insulin resistance, type 2 diabetes, obesity, metabolic syndrome, and cardiovascular disease. Men with type 2 diabetes have been shown to have significantly lower testosterone levels than men without diabetes. Several forms of testosterone replacement therapy (eg, oral, injectable, buccal, transdermal preparations) are available for use in the United States. The primary goals of testosterone therapy are to restore physiologic testosterone levels and reduce the symptoms of hypogonadism. Testosterone therapy may be a viable option in some men with diabetes and low testosterone; however, clinicians must be aware of contraindications to therapy (eg, prostate cancer and male breast cancer), implement appropriate monitoring procedures, and ensure that patient expectations are realistic regarding treatment outcome. Data suggest that testosterone therapy may have a positive effect on bones, muscles, erythropoiesis and anemia, libido, mood and cognition, penile erection, cholesterol, fasting blood glucose, glycated hemoglobin, insulin resistance, visceral adiposity, and quality of life. Sexual health may be a window into men's health; thus, more effective communication strategies are needed between clinicians and men with diabetes to ensure that sexual health topics are adequately addressed. Diabetes educators can play a key role in screening for low testosterone, providing relevant information to patients, and increasing clinician awareness of the need to address men's sexual health and implement appropriate strategies. Multidisciplinary care and individualized treatment are needed to optimize outcome.

Hyperandrogenism after transfer of topical testosterone gel: case report and review of published and unpublished studies

Topically applied testosterone gels are a widely used mode of testosterone replacement therapy. A concern associated with the use of testosterone gel is unintentional transfer to children or women by skin contact with the application site. We present a case of female hyperandrogenism most likely caused by transfer of testosterone gel used by her partner. Additionally, we searched the computerized database PUBMED and the FDA medical reviews for case reports and clinical trials concerning transfer risk. Several case reports and the results of clinical trials indicate that transfer of testosterone from gel-treated males to women and children is possible and clinically relevant. Thus, the potential of testosterone transfer in gel users should be recognized as a possible side effect of this form of testosterone replacement therapy.

Testosterone supplementation for hypogonadal men by the nasal route

Although multiple forms of testosterone replacement therapy are available to treat hypogonadism, none is ideal. This article reports on the pharmacokinetics of an innovative nasal formulation of testosterone in hypogonadal men. The first study was undertaken in eight men with a baseline total testosterone (TT) of 130.8 ± 87.4 ng/dL and examined the pharmacokinetics of nasal testosterone given in a single dose of 7.6 mg, 15.2 mg or 22.8 mg, respectively. The second study examined the pharmacokinetics of nasal testosterone (7.6 mg) given either twice or three times a day in 21 severely hypogonadal men (baseline TT in 20 patients <50 ng/dL, in one patient 152 ng/dL) for 14 days. The steady-state concentration of testosterone was within the normal range in all treatment groups, but only in the 3-times-a-day group was the 95% confidence interval completely within the physiological range. The average DHT level did not exceed the upper range of normal. The clinical global visual analogue scale improved in the whole group receiving testosterone (p < 0.001). All adverse events in both studies were of mild to moderate intensity and were evaluated as unlikely or not related to the administered study drug. No patients dropped out during treatment.Comparison with the normal circadian rhythm by computer modelling suggests that nasal testosterone can be used to mimic the normal diurnal pattern in eugonadal men. Thus, nasal testosterone can be administered safely to humans in doses that approximate serum concentrations in the normal physiological range.