Oral Testosterone Undecanoate Research Articles

Clinical Efficacy of the Long-Acting Intramuscular Compared to Oral Testosterone Undecanoate in Adult Men with Central Hypogonadism

Introduction. This study evaluates the clinical efficacy of androgen replacement therapy with the new long-acting intramuscular (i.m.) testosterone undecanoate (T.U.) in comparison to oral T.U. in adult men with hypogonadotropic hypogonadism. Patients and methods. In 41 patients with central hypogonadism (30 with pituitary tumors or craniopharyngiomas, 11 with non-tumor hypogonadism), aged 20-62 years, we evaluated, before and after androgen replacement therapy, morning serum total testosterone (T), hemoglobin, hematocrit, cholesterol, triglycerides (measured with commercial kits in venous blood sampled at 8.00-9.30 a.m) and the sexual dysfunction (SD) by questions on libido, frequency and quality of erections. Results. In group A, including 28 patients treated with oral T.U. median dose 120 mg/day (range 80-160) in 3 divided doses, for 4-60 (median 14) months, T rose from 0.37 ± 0.40 ng/mL (mean ± standard deviation) to 1.43 ± 1.36 ng/mL (p<0.01), reaching normal levels only in 4 patients (14%). In group B, including 20 patients treated with 1000 mg i.m. T.U. at 12 weeks intervals, for 1-12 (median 6) months, T rose from 0.88 ± 0.83 ng/mL to 5.88 ± 3.50 ng/ml (p<0.01). T was low in 1 patient (5%) and above normal in 6 patients (30%). A subgroup (C) of 7 patients was switched from oral to i.m.T.U. T was higher after i.m. than after oral T.U in group B vs. A and within subgroup C (p < 0.01). SD improved in 7/16 patients (43.7 %) on oral T.U. and in 11/12 patients (91.6%) on i.m. T.U (p < 0.05). Hematocrit increased significantly from baseline in both groups, while serum cholesterol and triglycerides did not change significantly on either T.U. treatment. Conclusions. Clinical efficacy, judged by normal morning T and sexual dysfunction improvement, was reached in over 90% of patients with central hypogonadism after i.m.T.U. and in less than half after oral T.U.

Clinical efficacy of the long-acting intramuscular compared to oral testosterone undecanoate in adult men with central hypogonadism

Introduction. This study evaluates the clinical efficacy of androgen replacement therapy with the new long-acting intramuscular (i.m.) testosterone undecanoate (T.U.) in comparison to oral T.U. in adult men with hypogonadotropic hypogonadism. Patients and methods. In 41 patients with central hypogonadism (30 with pituitary tumors or craniopharyngiomas, 11 with non-tumor hypogonadism), aged 20-62 years, we evaluated, before and after androgen replacement therapy, morning serum total testosterone (T), hemoglobin, hematocrit, cholesterol, triglycerides (measured with commercial kits in venous blood sampled at 8.00-9.30 a.m) and the sexual dysfunction (SD) by questions on libido, frequency and quality of erections. Results. In group A, including 28 patients treated with oral T.U. median dose 120 mg/day (range 80-160) in 3 divided doses, for 4-60 (median 14) months, T rose from 0.37 ± 0.40 ng/mL (mean ± standard deviation) to 1.43 ± 1.36 ng/mL (p<0.01), reaching normal levels only in 4 patients (14%). In group B, including 20 patients treated with 1000 mg i.m. T.U. at 12 weeks intervals, for 1-12 (median 6) months, T rose from 0.88 ± 0.83 ng/mL to 5.88 ± 3.50 ng/ml (p<0.01). T was low in 1 patient (5%) and above normal in 6 patients (30%). A subgroup (C) of 7 patients was switched from oral to i.m.T.U. T was higher after i.m. than after oral T.U in group B vs. A and within subgroup C (p < 0.01). SD improved in 7/16 patients (43.7 %) on oral T.U. and in 11/12 patients (91.6%) on i.m. T.U (p < 0.05). Hematocrit increased significantly from baseline in both groups, while serum cholesterol and triglycerides did not change significantly on either T.U. treatment. Conclusions. Clinical efficacy, judged by normal morning T and sexual dysfunction improvement, was reached in over 90% of patients with central hypogonadism after i.m.T.U. and in less than half after oral T.U.

Effects of Oral Testosterone Treatment on Myocardial Perfusion and Vascular Function in Men With Low Plasma Testosterone and Coronary Heart Disease

Intracoronary testosterone infusions induce coronary vasodilatation and increase coronary blood flow. Longer term testosterone supplementation favorably affected signs of myocardial ischemia in men with low plasma testosterone and coronary heart disease. However, the effects on myocardial perfusion are unknown. Effects of longer term testosterone treatment on myocardial perfusion and vascular function were investigated in men with CHD and low plasma testosterone. Twenty-two men (mean age 57 ± 9 [SD] years) were randomly assigned to oral testosterone undecanoate (TU; 80 mg twice daily) or placebo in a crossover study design. After each 8-week period, subjects underwent at rest and adenosine-stress first-pass myocardial perfusion cardiovascular magnetic resonance, pulse-wave analysis, and endothelial function measurements using radial artery tonometry, blood sampling, anthropomorphic measurements, and quality-of-life assessment. Although no difference was found in global myocardial perfusion after TU compared with placebo, myocardium supplied by unobstructed coronary arteries showed increased perfusion (1.83 ± 0.9 vs 1.52 ± 0.65; p = 0.037). TU decreased basal radial and aortic augmentation indexes (p = 0.03 and p = 0.02, respectively), indicating decreased arterial stiffness, but there was no effect on endothelial function. TU significantly decreased high-density lipoprotein cholesterol and increased hip circumference, but had no effect on hemostatic factors, quality of life, and angina symptoms. In conclusion, oral TU had selective and modest enhancing effects on perfusion in myocardium supplied by unobstructed coronary arteries, in line with previous intracoronary findings. The TU-related decrease in basal arterial stiffness may partly explain previously shown effects of exogenous testosterone on signs of exercise-induced myocardial ischemia.

Recent trends in the treatment of testosterone deficiency syndrome

Testosterone deficiency syndrome (TDS) is defined as a clinical and biochemical syndrome associated with advancing age and is characterized by typical symptoms and deficiency in serum testosterone levels. TDS is a result of the interaction of hypothalamo-pituitary and testicular factors. Now, treatment of TDS with testosterone is still controversial due to a lack of large, controlled clinical trials on efficacy. The risks of treatment with testosterone appear to be minimal, although long-term studies on the safety of testosterone therapy are lacking. The aim of the therapy is to establish a physiological concentration of serum testosterone in order to correct the androgen deficiency, relieve its symptoms and prevent long-term sequelae. All of the available products, despite their varying pharmacodynamic and pharmacokinetic profiles, are able to reach this goal. Newer testosterone patches seem not to cause severe skin irritation. Testosterone gels minimize the skin irritation while providing flexibility in dosing and a low discontinuation rate. Oral testosterone undecanoate (TU) is free of liver toxicity. Recent formulation of oral TU markedly increased shelf-live, a major drawback in the older preparation. Producing swings in testosterone levels rising rapidly to the supraphysiological range is not the case with the new injectable long-acting preparation of TU. To be able to rapidly react and stop treatment in cases where side-effects and contraindications are detected, the short-acting transdermal and oral delivery modes have certain advantages. However, there is no evidence that the use of an injectable long-acting TU in men with TDS has limitations in clinical application for this reason. The use of dehydroepiandrosterone is still controversial because of a lack of well designed long-term trials, although some recent studies suggest positive effects on various body systems. Only a few studies have been carried out to investigate the effect of hCG (human chorionic gonadotropin) in TDS with some positive results on various body systems.

Transient Scrotal Hyperthermia and Levonorgestrel Enhance Testosterone-Induced Spermatogenesis Suppression in Men through Increased Germ Cell Apoptosis

In rodents and monkeys, a combination of hormonal and physical agents accelerates germ cell death. A "proof of concept" study was performed to investigate whether addition of heat exposure or a progestin to an androgen induces germ cell death and more complete and rapid spermatogenesis suppression. A randomized clinical trial was performed at academic medical centers. We treated four groups of healthy male volunteers (18 per group) for 18 wk: 1) testosterone undecanoate (TU) 1000 mg im (first dose), followed by 500 mg im every 6 wk; 2) submersion of scrota at 43 C in water for 30 min/d for 6 consecutive days; 3) TU plus heat; and 4) TU plus oral levonorgestrel (LNG) 250 microg/d. Semen parameters, testicular histology, and germ cell apoptosis were the main outcome measures. Heat alone and TU plus heat suppressed sperm counts more than TU alone by wk 6. By wk 9, recovery began in the heat only group, whereas spermatogenesis remained suppressed in the TU plus heat group. Oral LNG plus TU suppressed spermatogenesis earlier and more severely than TU alone. At wk 2, significantly greater germ cell apoptosis occurred in heat and heat plus TU subjects, but not in subjects without heat treatment, compared with pretreatment subjects. By 9 wk, markedly smaller seminiferous tubule diameters and fewer spermatocytes and spermatids were noted in all 12 biopsies from men receiving TU, TU plus LNG, with most dramatic differences for the TU plus heat group, whereas no differences from pretreatment biopsies were observed in men who received heat treatment only. Heat causes a rapid and transient suppression of spermatogenesis. TU plus heat resulted in low-sperm output that was maintained by continuous treatment with TU. Addition of an oral progestin accelerated spermatogenesis suppression by TU alone. Increased germ cell apoptosis contributed to suppression of spermatogenesis.

The effect of food composition on serum testosterone levels after oral administration of Andriol® Testocaps®

ObjectiveAndriol® Testocaps® is a new oral formulation of testosterone undecanoate (TU) for treatment of hypogonadism. As TU is taken up by the intestinal lymphatic system, both the presence and the composition of food influence the absorption. The aim of this study was to investigate the effect of food composition on the pharmacokinetics of oral TU.DesignAn open-label, single-centre, four-way crossover study. With a washout period of 6–7 days, 80 mg TU was administered in the morning 5 min after consuming each of four different meals in a randomized order (A: 230 kcal, 0·6 g lipid; B: 220 kcal, 5 g lipid; C: 474 kcal, 19 g lipid; D: 837 kcal, 44 g lipid).PatientsTwenty-four postmenopausal volunteers.MeasurementsSerial blood samples were collected until 24 h after dosing to determine testosterone and dihydrotestosterone (DHT) by gas chromatography-mass spectroscopy (GC-MS).ResultsThe bioavailability of testosterone after a low-calorie meal containing 0·6 g lipid or 5 g lipid was relatively low, the area under the concentration–time curve (AUC0–tlast) for testosterone being 30·7 and 43·5 nmol h/l, respectively. The bioavailability of testosterone after a meal containing 19 g lipid was considerably higher (AUC0–tlast = 146 nmol h/l), whereas increasing the lipid content to 44 g lipid did not further increase the bioavailability of testosterone (AUC0–tlast = 154 nmol h/l).ConclusionApproximately 19 g of lipid per meal efficiently increases absorption of testosterone from oral TU. Therefore, coadministration with a normal rather than a fatty meal is sufficient to increase serum testosterone levels when using oral TU.

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

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.

Testosterone treatment comes of age: new options for hypogonadal men

Male hypogonadism is one of the most frequent, but also most underdiagnosed, endocrinopathies. However, the required testosterone treatment is simple and very effective if properly administered. Although testosterone has been available for clinical use for seven decades, until quite recently the treatment modalities were far from ideal. Subdermal testosterone pellets require minor surgery for insertion and often cause local problems. The injectable testosterone enanthate, for a long period the most frequently used mode of administration, lasts for two to four weeks, but produces supraphysiological levels initially and low levels before the next injection. The oral testosterone undecanoate has to be taken three times daily, has an uncertain absorption pattern and results in peaks and valleys of serum testosterone levels throughout the day. With the advent of transdermal testosterone preparations, the desired physiological serum levels could be achieved for the first time. Scrotal testosterone patches were the first to fulfil this requirement. These were followed by nonscrotal skin patches, which, however, cause considerable skin reactions including erythema and blisters. Recently introduced, invisible transdermal testosterone gels increased the intervals of application and are now slowly replacing other modalities. A mucoadhesive buccal testosterone tablet with sustained release is also a recent competing modality. Finally, injectable testosterone undecanoate in castor oil was made into a real depot preparation requiring only four injections per year for replacement therapy. These new preparations with a desired pharmacokinetic testosterone profile give the patient a real choice and make treatment easier. Based on pharmacogenetic considerations taking the androgen receptor polymorphism into account, treatment may be individualized for each patient in the future.

Testosterone Replacement Therapy for Male Aging: ASA Position Statement

Testosterone Replacement Therapy for Male Aging: ASA Position Statement

Use of isotope ratio mass spectrometry to detect doping with oral testosterone undecanoate: Inter-individual variability of 13C/ 12C ratio

The metabolic effect of multiple oral testosterone undecanoate (TU) doses over 4 weeks was assessed in seven voluntary men. The protocol was designed to detect accumulation of the substance by choosing the appropriate spot urines collections time and to study the urinary clearance of the substance after weeks of treatment. Urines were analysed by a new GC/C/isotope ratio mass spectrometry (IRMS) method to establish the δ 13C-values of testosterone metabolites (androsterone and etiocholanolone) together with an endogenous reference compound (16(5α)-androsten-3α-ol). The significant differences in inter-individual metabolism following TU intake was illustrated by large variations in δ 13C-values of both T metabolites (maximum Δ δ 13C-values = 5.5‰), as well as by very stable longitudinal T/E profiles and carbon isotopic ratios in the first hours following administration. According to T/E ratios and δ 13C-values, the washout period after 80 mg TU intake was less than 48 h for all subjects and no accumulation phenomenon was observed upon chronic oral administration.

Combined use of androgen and sildenafil for hypogonadal patients unresponsive to sildenafil alone

To investigate the therapeutic effect of androgen on hypogonadal patients unresponsive to sildenafil alone. In total, 32 hypogonadal patients with erectile dysfunction (ED), initially had an inadequate response to sildenafil (100 mg). Oral testosterone undecanoate (Restandol, 80 mg, bid or tid) alone was supplied for 2 months, and if patients could not achieve a satisfactory erection, combined use of testosterone and sildenafil was continued thereafter. Total testosterone (TT), free testosterone (FT), and the parameters of the International Index of Erectile Function (IIEF), International Prostate Symptom Score (IPSS), and uroflow rate (UFR) were assessed. Eleven patients (34.3%) achieved satisfactory erectile function after testosterone replacement only. Another 12 (37.5%) patients experienced satisfactory intercourse after combined therapy. Serum TT and FT levels significantly increased after the use of testosterone alone (415+/-163 vs 220+/-101 ng/dl, P<0.01; 10.4+/-4.6 vs 5.1+/-1.9 ng/dl; P<0.01, respectively) and the combined use of testosterone and sildenafil (498+/-178 vs 220+/-101 ng/dl, P<0.01; 11.7+/-4.6 vs 5.1+/-1.9 ng/dl, P<0.001, respectively); as did the IIEF score (14.8+/-6.8 vs 12.6+/-7.5, P<0.01, 17.5+/-5.2 vs 12.6+/-7.5, P<0.001, respectively). However, no statistical differences were demonstrated for IPSS or UFR. In conclusions, one-third of hypogonadal patients with ED who failed to respond to sildenafil, responded to testosterone alone, another third responded to sildenafil again after normalization of testosterone. So, in hypogonadal patients with ED, androgen supplementation is first-line therapy. If patients are unresponsive to androgen alone or sildenafil alone, combined use may improve erectile function and enhance the therapeutic effect of PDE-5 inhibitors.

443 PUBLICATION A novel weekly sliding regimen of docetaxel to treat metastatic breast cancer (MBC) patients with severe hepatic or haematological dysfunction

Long-term exposure to benzene can potentially result in severe haematotoxicities, including pancytopaenia, aplastic anaemia and myelodysplastic syndrome, which are often accompanied by life-threatening symptoms and high mortality. Previous studies demonstrate that benzene-induced haematotoxicities are immune-mediated and that cyclosporin A is a prominent treatment in acquired aplastic anaemia. This study aims to evaluate the potential role of cyclosporin A immunosuppressive therapy for severe benzene-induced haematotoxicity. Between January 2002 and December 2008, 41 patients with severe benzene-induced haematopoietic disorders from five hospitals were enrolled in the study, 22 patients received cyclosporin A, supportive treatments and/or oral testosterone undecanoate, 19 patients were treated with supportive treatments and/or oral testosterone undecanoate as the control group, and a 6-month follow-up was conducted. The results showed that in the cyclosporin A group, 19 of 22 patients (86.36%) had responded to the treatments completely or partially with increased platelets, white blood cells and hemoglobulin counts by the fourth week (P = 0.005), the sixth week (P = 0.001) and the third month post-treatment (P = 0.034), respectively. However, in the control group treated by supportive methods, only 5 of 19 patients (26.32%) responded to the treatments partially (P < 0.001). Cyclosporin A in conjunction with supportive treatments may be an effective treatment modality for patients with severe benzene-induced haematopoietic disorders, which in turn implies that these haematotoxicities are immune-mediated.

Effects of combined estrogen/testosterone therapy on bone and body composition in oophorectomized women

Objective. To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen therapy on bone markers, bone mineral density and body composition in oophorectomized women.Methods. Fifty women, 45–60 years old, who had undergone a hysterectomy and bilateral salpingo-oophorectomy for benign disorders, were randomly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily. Twenty-four weeks later, cross-over was performed to the other treatment regimen. Forty-four women completed the study. Their serum concentrations of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, osteocalcin, carboxyterminal telopeptide aminoterminal (ICTP), of type I collagen propeptide of type I procollagen (PICP) and interleukin (IL)-1 receptor antagonist were measured at baseline and after 24 weeks of both treatments, as were also their body mass index (BMI) and blood pressure. Bone mineral density of the total body, spine and hip and total body fat, total lean body mass, trunk fat and trunk lean mass were determined by dual-energy X-ray absorptiometry measurements at baseline and after 24 weeks of both regimens.Results. During treatment, the addition of testosterone counteracted the decrease in IGF-I and PICP seen with estrogen therapy alone. Osteocalcin and ICTP were significantly reduced to the same extent by both therapies. No change ocurred in the IL-1 receptor antagonist. A significant increase was seen in total lean body mass with the estrogen/testosterone regimen, but the total fat mass, trunk lean or fat mass remained unchanged after 24 weeks of both treatments. No effect was detected on total, hip or spinal bone mineral density after treatment with estrogen alone or estrogen/testosterone. Likewise, BMI and blood pressure were unaffected.Conclusions. The addition of testosterone to oral estrogen might have positive effects on bone as suggested by the fact that it counteracted the decline in IGF-I and PICP levels. An anabolic effect on muscle was reflected by an increase in the total lean body mass. No adverse effects were noted on BMI, fat distribution or blood pressure during the 6-month treatment with oral testosterone undecanoate.

Topical Androgen Substitution

Traditionally, the most widely used testosterone formulations are depot injections of testosterone enantate or cipionate and oral testosterone undecanoate; less frequently used are testosterone implants or sublingual preparations and, more recently, intramuscular testosterone undecenoate. Oral testosterone undecanoate, in the usual dosage of 160–240 mg/day in 2–3 divided doses, yields low normal plasma testosterone levels with increased dihydrotestosterone (DHT) levels, whereas depot injections of testosterone 200mg (every 2 weeks) cause transient supraphysiologic testosterone levels, followed by a slow decrease to low-normal level, the fluctuations being perceived as unpleasant by the patients. Implants induce normal testosterone levels over a period of several months; however, these require surgical removal in the event of serious adverse effects, especially in elderly males. Over the last decade, several transdermal testosterone formulations delivering about 5mg of testosterone per day have become available, at first as scrotal, and later as non-scrotal transdermal patches. They have the advantage of providing physiologic testosterone levels, mimicking even normal nychthemeral variations, and of ease of stopping treatment in the event of adverse effects. The disadvantages are problems with patch adherence and local irritation. More recently, transdermal gels, containing 1–2.5% of testosterone, have come on the market. These allow for better dose flexibility, providing physiologic testosterone levels over the nycthemere. In addition, DHT gels, supposed to have less stimulating effects on the prostate, have recently become available. The most recent development is a testosterone bioadhesive buccal system, which, in a dose of 10–30 mg/day, induces physiologic testosterone levels in the majority of hypogonadal men, with minimal adverse effects. Only data concerning short-term studies are available and more experience is required before the advantages of this treatment modality can be evaluated objectively. The clinical effects of the different testosterone formulations are similar, provided physiologic levels are obtained.

Evolution of delivery systems for testosterone administration

Hypogonadism, especially in aging men, is being identified and treated more frequently. Androgen replacement therapy began in the 1930s, and oral and intramuscular testosterone preparations were the primary products until the 1980s. Because of toxicity with oral medications and serum levels outside the normal range with injectable preparations, alternative approaches have been developed. Outside the United States, many patients receive oral testosterone undecanoate, which requires multiple doses per day and produces inconsistent serum levels. Transdermal preparations, both patches and gels, provide excellent serum levels and safety, although patches may cause skin irritation. Implantable pellets and buccal tablets provide additional choices for androgen replacement. Testosterone gel provides excellent patient tolerability and efficacy with somewhat higher costs and low potential for transfer to contacts.

Effect of oral testosterone undecanoate on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status

Objectives: The effects of supplemental testosterone on cognition, mood and wellbeing in ageing men are unclear. This study aimed to assess the effect of 12-months of oral testosterone supplementation on cognitive function, mood and quality of life in elderly men with low-normal gonadal status, not specifically selected for cognitive or mood defects. Methods: A standard oral dose (80 mg twice daily) of testosterone undecanoate (TU) or placebo was administered for one year to 76 healthy men 60 years or older. All men had a free testosterone index (FTI) of 0.3–0.5, which represents a value below the normal lower limit for young men (19–30 years), but remains within the overall normal male range. A neuropsychological assessment including the trail making test (part B), visuospatial (VSP) block design test, mini mental state exam (MMSE), Geriatric Depression Scale (GDS), a 5-point Likert and a 10-point visual analogue quality of life (QoL) scale, along with serum hormone measurements were obtained at baseline, 6, and 12 months. Results: Although calculated bioavailable testosterone (cBT) and FTI were higher, and muscle mass increased after 12 months, there was no difference in scores on the trail making or VSP block tests, the MMSE, GDS or either of the QoL scales between the testosterone and placebo group. There was no relationship between baseline cBT or FTI and treatment effect for any of the outcome measures. Conclusions: 12-month supplementation with oral TU does not affect scores on visuospatial tests or mood and quality of life scales in older men with low-normal gonadal status.

IRAD2 : Insuffisant respiratoire à domicile 2 (2 e étude) effets d’une réhabilitation à domicile chez l’insuffisant respiratoire chronique dénutri

The IRAD2 trial is evaluating a 3-month home intervention which includes education, oral supplements, exercise and androgenic steroids in undernourished patients with chronic respiratory failure. The main objective is to increase the six-minute walking distance by more than 50 m with an improvement in health-related quality-of-life. Secondary end-points include a reduction in exacerbation rates by 25%, a reduction in health-related costs and an increase in survival during the year following intervention. This interventional, multi-centre, prospective, two-armed parallel, controlled trial is being conducted in 200 patients. In both groups, "Control" and "Rehabilitation", 7 home visits are scheduled during the 3-month intervention for education purpose. In the "Rehabilitation" group, patients will receive 160 mg/d of oral testosterone undecanoate in men, 80 mg/d in women, oral dietary supplements (563 kcal/d) and exercises on an ergometric bicycle 3 to 5 times a week. In the event of significant responses to intervention, this trial would validate a comprehensive and global home-care for undernourished patients with chronic respiratory failure combining therapeutic education, oral supplements, androgenic substitution and physical activity.

Testosterone therapy - what, when and to whom?

Testosterone therapy has been used for more than 60 years in the treatment of male hypogonadism. The classical forms of hypogonadism are comprised of primary testicular failure or insufficient testicular stimulation due to the lack of pituitary gonadotropins. Typical causes of primary hypogonadism are Klinefelter's syndrome, anorchia or acquired disturbances of testicular function. Secondary hypogonadism is characterized by insufficient production of pituitary gonadotropins, due either to pituitary failure or defects at the hypothalamic level. It is unequivocally accepted in clinical practice that any male with inadequately low testosterone production for his age will require androgen therapy. In addition to the classical forms of hypogonadism, the past decade of research has clearly demonstrated that, with increasing age, many men will suffer from decreasing testosterone production. About 15-25% of men over the age of 50 years will experience serum testosterone levels well below the threshold considered normal for men between 20 and 40 years of age. Studies substituting testosterone in elderly men with low serum testosterone have shown that men with clinical symptoms identical to the symptomatology of classical hypogonadism will benefit most from such therapy. Therefore, it is the general consensus to treat men with age-related hypogonadism only when clinical symptoms are present that can be potentially corrected by testosterone administration. Until recently, intramuscular injections of esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. The introduction of testosterone patches has not challenged this approach, since many users of patches suffer from moderate to severe skin reactions. Some oral testosterone formulations have proven to be problematic, as absorption can be variable, bioavailability is frequently poor, due to the first-pass effect of the liver, and frequent administration is often required<citeref rid="b1"><emph>1</emph></citeref>. Oral testosterone undecanoate avoids, at least partially, the first-pass effect of the liver. However, plasma testosterone levels generally undergo large fluctuations<citeref rid="b2"><emph>2</emph></citeref>. The large fluctuations in serum testosterone levels caused by conventional intramuscular injections result in unsatisfactory shifts in mood and sexual function in some men, which, combined with the frequency of injections, make the intramuscular mode of delivery far from ideal. Recently, a hydroalcoholic gel containing 1% testosterone has proven to be as efficient as a testosterone patch, but with fewer side-effects and a higher grade of patient satisfaction<citeref rid="b3"><emph>3</emph></citeref>-<citeref rid="b4"></citeref><citeref rid="b5"><emph>5</emph></citeref>. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and correct the signs and symptoms of hypogonadism. The gel has been shown to be effective and successful in patients in the United States, who have benefited from its availability for almost 3 years. In the near future, intramuscular injections of testosterone undecanoate will become commercially available. Such injections have a very favorable pharmacokinetic profile, with one injection every 3 months maintaining serum testosterone well within the normal range. In phase III studies, intramuscular testosterone undecanoate proved to be as efficient as testosterone enanthate, with only one-quarter of the number of injections required and more stable serum testosterone levels. Thus, the new application modes - hydroalcoholic gel (for example, Testogel®, Schering AG, Germany) and intramuscular testosterone undecanoate (Nebido®, Schering AG, Germany) - appear to be the methods of choice in the near future, one being very suitable for hormone therapy in elderly men, the other for long-term substitution in classical forms of hypogonadism.

Androgen replacement therapy: present and future.

The major goal of androgen substitution is to replace testosterone at levels as close to physiological levels as is possible. For some androgen-dependent functions testosterone is a pro-hormone, peripherally converted to 5alpha-dihydrotestosterone (DHT) and 17beta-estradiol (E2), of which the levels preferably should be within normal physiological ranges. Furthermore, androgens should have a good safety profile without adverse effects on the prostate, serum lipids, liver or respiratory function, and they must be convenient to use and patient-friendly, with a relative independence from medical services. Natural testosterone is viewed as the best androgen for substitution in hypogonadal men. The reason behind the selection is that testosterone can be converted to DHT and E2, thus developing the full spectrum of testosterone activities in long-term substitution. The mainstays of testosterone substitution are parenteral testosterone esters (testosterone enantate and testosterone cipionate) administered every 2-3 weeks. A major disadvantage is the strongly fluctuating levels of plasma testosterone, which are not in the physiological range at least 50% of the time. Also, the generated plasma E2 is usually supraphysiological. A major improvement is parenteral testosterone undecanoate producing normal plasma levels of testosterone for 12 weeks, with normal plasma levels of DHT and E2 also. Subcutaneous testosterone implants provide the patient, depending on the dose of implants, with normal plasma testosterone for 3-6 months. However, their use is not widespread. Oral testosterone undecanoate dissolved in castor oil bypasses the liver via its lymphatic absorption. At a dosage of 80 mg twice daily, plasma testosterone levels are largely in the normal range, but plasma DHT tends to be elevated. For two decades transdermal testosterone preparations have been available and have an attractive pharmacokinetic profile. Scrotal testosterone patches generate supraphysiological plasma DHT levels, which is not the case with the nonscrotal testosterone patches. Transdermal testosterone gel produces fewer skin irritations than the patches and offers greater flexibility in dosage. Oromucosal testosterone preparations have recently become available. Testosterone replacement is usually of long duration and so patient compliance is of utmost importance. Therefore, the patient must be involved in the selection of type of testosterone preparation. Administration of testosterone to young individuals has almost no adverse effects. With increasing age the risk of adverse effects on the prostate, the cardiovascular system and erythropoiesis increases. Consequently, short-acting testosterone preparations are better suited for aging androgen-deficient men.

Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol formulations in conscious lymph duct-cannulated dogs.

Orally administered testosterone (T) is ineffective in the treatment of male androgen deficiency syndromes due to extensive presystemic first-pass metabolism. In contrast, the lipophilic long-chain ester testosterone undecanoate (TU) exhibits androgenic activity that has been attributed to formation of T via systemic hydrolysis of lymphatically transported TU. However, there are no definitive data regarding the oral bioavailability of TU or the extent to which lymphatically transported TU contributes to the systemic availability of T after oral TU administration. This report describes the application of stable isotope methodology in a thoracic lymph duct-cannulated dog model to study the oral bioavailability and lymphatic transport of TU after postprandial administration. When administered as either Andriol or Andriol Testocaps, the mean (+/-S.E., n = 4) absolute bioavailability of TU was 3.25 +/- 0.48 and 2.88 +/- 0.88%, respectively, and lymphatically transported TU accounted for between 91.5 and 99.7% of the systemically available ester. Model-independent pharmacokinetic analysis indicated that 83.6 +/- 1.6 and 84.1 +/- 8.2% of the systemically available T, resulting from Andriol or Andriol Testocaps, respectively, was due to systemic hydrolysis of lymphatically transported TU. These data demonstrate that intestinal lymphatic transport of TU produces increased systemic exposure of T by avoiding the extensive first-pass effect responsible for the inactivation of T after oral administration.