Effects of long-term oral testosterone undecanoate therapy on urinary symptoms: data from a 1-year, placebo-controlled, dose-ranging trial in aging men with symptomatic hypogonadism.

BACKGROUND: There has been a longstanding question as to whether testosterone therapy could precipitate or worsen urinary symptoms in aging men. We investigated the effects of 1-year oral testosterone undecanoate (TU) therapy on urinary symptoms in aging, hypogonadal men. METHODS: A total of 322 men ≥50 years with symptomatic testosterone deficiency participated in a 1-year, randomized, multicenter, double-blind trial. Patients received placebo or oral TU 80 mg/day, 160 mg/day, or 240 mg/day. RESULTS AND LIMITATIONS: Compared with placebo, treatment with oral TU at doses of 80 mg/day and 160 mg/day resulted in no significant change in IPSS urinary symptoms or quality of life (QoL) scores. Treatment with oral TU 240 mg/day led to a statistically significant, but clinically insignificant, improvement in IPSS total score and a significant improvement in IPSS QoL score. None of the TU doses tested had a significant effect on PSA or PV. CONCLUSIONS: Long-term oral TU therapy had no deleterious effects on IPSS total score and did not change PV and PSA in aging, hypogonadal men. Oral TU therapy at a dose of 240 mg/day may even improve IPSS QoL score.

Effects of oral testosterone undecanoate therapy on bone mineral density and body composition in 322 aging men with symptomatic testosterone deficiency: a 1-year, randomized, placebo-controlled, dose-ranging study.

OBJECTIVE: We investigated the effects of oral testosterone undecanoate (TU) on bone mineral density (BMD), lean body mass (LBM) and body fat mass (BFM) in aging men with symptomatic testosterone deficiency (TD). METHODS: Three hundred twenty-two men ≥50 years with TD symptoms and calculated free testosterone <0.26 nmol/L participated in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to placebo, oral TU 80 mg/d, oral TU 160 mg/d, or oral TU 240 mg/d, administered as divided doses with normal meals. BMD of the hip and lumbar spine were evaluated by dual energy X-ray absorptiometry (DEXA), and body composition (LBM and BFM) by whole body DEXA. RESULTS: Oral TU significantly increased BMD at Month 12 at the lumbar spine (240 mg/d), total hip (240 mg/d), and trochanter and intertrochanter (160 and 240 mg/d) compared with placebo. Oral TU significantly increased LBM at Months 6 and 12 for all oral TU groups compared with placebo. BFM significantly decreased at Month 6 (all oral TU groups) and Month 12 (160 mg/d) compared with placebo. The effects on BMD and body composition showed a clear dose response. CONCLUSIONS: Treatment with oral TU led to improvement in BMD, LBM and BFM in aging men with symptomatic TD.

Pharmacokinetic evaluation of three different intramuscular doses of nandrolone decanoate: analysis of serum and urine samples in healthy men.

The pharmacokinetics of nandrolone in serum and urine were investigated in healthy young men after a single im injection of 50 mg (n = 20), 100 mg (n = 17), or 150 mg (n = 17) nandrolone decanoate. Blood samples were collected before treatment and for up to 32 d after dosing. In addition, in the 50- and 150-mg groups, 24-h urine samples were collected before treatment and on d 1, 7, and 33 after treatment; in the 150-mg group, additional samples were collected after 3 and 6 months. Serum concentrations and the area under the curve of nandrolone increased proportionally with the dose administered. The peak serum concentration ranged from 2.14 ng/ml in the 50-mg group to 4.26 ng/ml in the 100-mg group and 5.16 ng/ml in the 150-mg group. The peak serum concentration was reached after 30 h (50 and 100 mg) and 72 h (150 mg), whereas the terminal half-life was 7-12 d. In urine, pretreatment concentrations of 19-norandrosterone (19-NA) and/or 19-noretiocholanolone (19-NE) were detected in five of 37 subjects (14%). In the 50-mg group, 19-NA and/or 19-NE could be detected at least until 33 d after injection in 16 of 17 subjects (94%). In the 150-mg group, who were presumed to have not previously used nandrolone, nandrolone metabolites could be detected for up to 6 months in eight of 12 subjects (67%) for 19-NE and in 10 of 12 subjects (83%) for 19-NA.

A pilot efficacy study with a single-rod contraceptive implant (Implanon) in 200 Indonesian women treated for < or = 4 years.

In this 4-year open-label, noncomparative, single-center pilot efficacy study, the contraceptive efficacy, safety, bleeding pattern and acceptability of Implanon was studied in 200 sexually active women of proven fertility in Indonesia. All subjects received the single-rod subdermal implant Implanon, which contains 68 mg etonogestrel (3-keto-desogestrel), with an initial release rate of 67 micrograms etonogestrel/day. Contraceptive efficacy was analyzed by calculation of the pregnancy rate, bleeding patterns were determined by the 90-day reference period method, and acceptability by the discontinuation rate. No in-treatment pregnancies were reported during 658.4 women-years of exposure, resulting in a Pearl Index of 0.0 (95% CI 0.0-0.6). The overall bleeding pattern was acceptable, with no discontinuations because of irregular bleeding. Incidence of irregular bleeding was highest during the first two reference periods and decreased thereafter. Amenorrhea was experienced by 7%-12% of subjects during years 1 and 2, by 5%-7% during year 3, and by 2%-5% during year 4, with one discontinuation because of amenorrhea. No clinically significant changes were reported for systolic and diastolic blood pressure, body mass index, and hemoglobin level. Three adverse experiences were related to treatment and resulted in discontinuation (two headaches and one dyspnea). One difficult implant removal was reported. In conclusion, this pilot efficacy study indicates that Implanon provides excellent contraceptive reliability and an acceptable bleeding pattern. Overall safety and acceptability are good, as suggested by the low incidence of adverse experiences and the low discontinuation rate.

A randomized controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75 microgram desogestrel or 30 microgram levonorgestrel.

The effects of two progestogen-only pills containing either 75 microgram desogestrel (DSG) or 30 microgram levonorgestrel (LNG) on hemostasis were investigated in a double-blind, randomized, controlled study of seven treatment cycles in 78 healthy women. DSG reduced factor VII activity (p < 0.05) and prothrombin fragment 1+2 (p < 0.05) and increased protein S (p < 0.001). LNG reduced factor VII activity (p < 0.01) and plasminogen activity (p < 0.01) and increased tissue-plasminogen activator (t-PA) (p < 0.05). At the end of the post-treatment cycle with DSG, protein S (p < 0.01) and t-PA (p < 0.05) were increased and plasminogen activity was decreased (p < 0.05), whereas with LNG, t-PA was increased (p < 0.001) and prothrombin fragment 1+2 (p < 0.05) and plasminogen activity (p < 0.001) were decreased. Between-group comparisons revealed higher values for DSG regarding the anticoagulatory parameter protein S at cycle 7 (p < 0.01) and post-treatment assessments (p < 0.05), and the fibrinolytic parameter plasmin-antiplasmin complex was higher with DSG at cycle 7 (p < 0.05) and at post-treatment (p < 0.05). Both preparations had comparable and potentially favorable effects of hemostasis, and may offer suitable hormonal contraception to women with a personal or family history of venous thromboembolic diseases.

Review of the endometrial safety during intravaginal treatment with estriol.

To gain more insight into whether intravaginal treatment of local urogenital complaints with the mild-acting oestrogen estriol is capable of inducing proliferation of the endometrium, the results of the clinical studies that have been published over the years have been pooled. Of a total of 19 studies that initially had been selected, four were excluded from the analysis because no baseline biopsies were available, two because endometriae had been evaluated using methods other than with histology, and one study because a sustained-release preparation was used. Pooling of 12 studies (214 subjects) revealed a reasonable amount of long-term data on intravaginal estriol treatment with 61 evaluable biopsies after 6 months and 58 after 12 months. In addition, 13 biopsies were available after 2 years. It appeared that intravaginal estriol treatment using the recommended dosages did not result in endometrial proliferation. All 337 post-baseline biopsies that have been reported in the literature were classified as atrophic. It can be concluded that single daily treatment with intravaginal estriol in the recommended doses in postmenopausal women is safe and without an increased risk of endometrial proliferation or hyperplasia. Consequently, there is no need to add sequential progestogens with these preparations and no withdrawal bleedings will be induced.

Bioequivalence assessment of three different estradiol formulations in postmenopausal women in an open, randomized, single-dose, 3-way cross-over study.

OBJECTIVE: The aim of the study was to assess the bioavailability of estradiol (E2) following oral, single-dose administration of equimolar doses of three HRT preparations in a 3-way cross-over study in postmenopausal women. METHODS: 18 healthy subjects were enrolled. Free E2 and estrone (E1) serum concentrations were determined using commercially available immunoassay kits. Bioequivalence testing was performed between the following oral formulations: (a) 1.5 mg E2 tablets versus 2 mg E2V tablets; and (b) 1.5 mg E2 plus 0.15 mg DSG tablets versus 1.5 mg E2 tablets. RESULTS: For both E2 and E1 the E2 tablet was bioequivalent with both the E2V and the E2/DSG tablet with respect to the rate and extent of absorption (bioavailability). Although the mean tmax values of the three tablet formulations were similar, the variability was too large to prove formal bioequivalence. CONCLUSION: E2 tablets and E2/DSG tablets were bioequivalent and also bioequivalence of E2 tablets with commercially available E2V was found, which ensures a sequential HRT preparation without large variations in estrogen serum concentrations.

Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.

OBJECTIVE: To investigate the effects of oral testosterone undecanoate (TU) on symptoms associated with late-onset hypogonadism (LOH). Design Multicenter, randomized, double-blind, placebo-controlled. METHODS: The study was performed in 14 study centers in seven European countries. Men > or =50 years (n=322) with symptoms of hypogonadism and testosterone deficiency (calculated free testosterone <0.26 nmol/l) were randomized and treated for 12 months with placebo or oral TU 80, 160 or 240 mg/day. Primary outcome was the total score on the Aging Males' Symptoms (AMS) rating scale after six months of treatment. RESULTS: Treatment of mild-to-moderate LOH symptoms in subjects with borderline hypogonadism with oral TU resulted in an improved total AMS score at month 6, but differences between groups were not statistically significant. There was greater improvement in subjects <60 years when compared with subjects > or =60 years (P=0.001), but baseline testosterone level had no influence on treatment response. The AMS sexual symptoms domain improved with oral TU 160 mg/day at months 6 (P=0.008) and 12 (P=0.012) compared with placebo, but not with 80 and 240 mg/day. Treatment was well-tolerated and there were no between-group differences in adverse events or drop-out rates. CONCLUSIONS: In one of the largest placebo-controlled studies of testosterone therapy in LOH, oral TU did not improve total AMS score in subjects with mild-to-moderate symptoms compared with placebo, except the sexual symptom sub-domain where a modest improvement was reported with oral TU 160 mg/day.

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

OBJECTIVE: Andriol 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. DESIGN: An 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). PATIENTS: Twenty-four postmenopausal volunteers. MEASUREMENTS: Serial blood samples were collected until 24 h after dosing to determine testosterone and dihydrotestosterone (DHT) by gas chromatography-mass spectroscopy (GC-MS). RESULTS: The 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 (AUC(0-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 (AUC(0-tlast) = 146 nmol h/l), whereas increasing the lipid content to 44 g lipid did not further increase the bioavailability of testosterone (AUC(0-tlast) = 154 nmol h/l). CONCLUSION: Approximately 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.

Effects of nandrolone decanoate compared with placebo or testosterone on HIV-associated wasting.

Objectives Current research is unclear about the most effective pharmacological agents for managing the loss of weight and fat-free mass common in HIV/AIDS. The aim of this study was to compare nandrolone decanoate with placebo and testosterone. Methods The study was a multicentre randomized double-blind placebo-controlled trial. Three hundred and three adult HIV-positive male patients with a weight loss of 5-15% in the last 12 months, or a body mass index of 17-19 kg/m(2), or a body cell mass/height ratio lower than 13.5 kg/m, were randomly assigned to receive nandrolone decanoate (150 mg), testosterone (250 mg) or placebo intramuscularly every 2 weeks for 12 weeks. Fat-free mass, weight, immune markers and perception of treatment were the main outcome measures. Results Treatment with nandrolone resulted in significantly greater increases in fat-free mass [mean increase 1.34 kg; 95% confidence interval (CI) 0.60; 2.08 kg] and in weight (mean increase 1.48 kg; 95% CI 0.82; 2.14 kg) compared with placebo. The mean increase in weight with nandrolone of 1.00 kg (95% CI 0.27; 1.74 kg) when compared with testosterone was significant, although the difference in fat free mass did not reach significance (mean increase 0.69 kg; 95% CI-0.13; 1.51 kg). Patient perception of benefit was significantly greater in the nandrolone group when compared with both the placebo and the testosterone groups. Conclusions Treatment with nandrolone decanoate increased body weight when compared with placebo and testosterone. Nandrolone decanoate treatment resulted in greater increases in fat-free mass than placebo and demonstrated a trend for a significant increase when compared with testosterone.

A randomized three-way cross-over study in healthy pituitary-suppressed women to compare the bioavailability of human chorionic gonadotrophin (Pregnyl) after intramuscular and subcutaneous administration.

The objective of this study was to compare the bioavailability of s.c. and i.m. administration of human chorionic gonadotrophin (HCG; Pregnyl). In a randomized, single-centre, three-way cross-over study, 18 healthy pituitary-suppressed volunteers were assigned to single HCG injections of 5000 and 10,000 IU i.m. and 10,000 IU s.c. Rate (Cmax, t(max)) and extent [area under curve from zero to infinity (AUC(0-infinity))] of absorption of HCG were determined. Serum immunoactive HCG increased from 0.4-0.5 IU/l at baseline to mean peak concentrations, which were reached 20 h after injection of 156 IU/l with 5000 IU i.m., of 307 IU/l with 10,000 IU i.m. and of 339 IU/l with 10,000 IU s.c. Eight days after administration, < 10% of the maximum HCG activity was found for each regimen. The elimination half-life (t(1/2)) was on average 32-33 h, irrespective of the treatment regimen. Intramuscular and s.c. injections of 10,000 IU HCG were bioequivalent with respect to AUC(0-infinity). The Cmax and t(max) were also similar between the two administration routes but bioequivalence could not be proven due to intersubject variability. Intramuscular doses of 5000 IU and 10,000 IU HCG were dose-proportional. Since s.c. HCG is bioequivalent to i.m. HCG with respect to extent of absorption (its major pharmacokinetic variable) and is well tolerated, the s.c. administration route may be effectively and safely used in assisted reproduction. Moreover, since s.c. injection can be performed by the patients themselves, acceptability may be enhanced.

The effects of two phasic oral contraceptives on hemostasis and platelet function.

OBJECTIVE: To compare the effects on hemostatic parameters of a combiphasic oral contraceptive containing desogestrel and ethinyl estradiol (DSG/EE) and a triphasic oral contraceptive containing levonorgestrel and ethinyl estradiol (LNG/EE). METHODS: In an open-label, randomized, group-comparative study in 10 healthy volunteers per treatment group, the effects on parameters of coagulation, anticoagulation, fibrinolysis, antifibrinolysis and platelet function were determined at baseline, after three treatment cycles, and after a post-treatment cycle. Changes from baseline were analyzed using a paired t-test, whereas between-group differences were analyzed by means of an analysis of co-variance. RESULTS: Both OC preparations induced modest changes of some coagulation, anticoagulation, fibrinolysis and antifibrinolysis parameters, although all mean values remained within the normal range. No significant effects were observed with either OC with respect to platelet function. Statistically significant differences between the two preparations could occasionally e observed: the concentrations of antithrombin II (AT-III) and Factor VII were higher with the DSG/EE preparation than with LNG/EE preparation at the end of treatment and AT-III activity, AT-III concentration, Factor X concentration, and plasminogen activity were higher with DSG/EE than with LNG/EE in the post-treatment cycle. CONCLUSIONS: Combiphasic DSG/EE and triphasic LNG/EE, both OCs with a comparable amount of EE per cycle, had no clinically significant effect on the overall hemostatic balance.

Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins.

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.

A randomized study on the effects of intramuscular injections with urinary gonadotrophins (Humegon or Pergonal) on pain, local redness and fever in infertile women opting for in-vitro fertilization.

The objective of this open, multicentre, randomized controlled study in women opting for in-vitro fertilization was to compare the occurrence of pain and redness at the injection site and of post-injection fever after i.m. injection with Humegon (n = 89) or Pergonal (n = 92). Assessments were scoring of pain and redness at the injection site and of post-injection fever during the next 24 h using self-administered questionnaires. Injection site pain was reported in 48.9% of injections with Humegon and in 44.9% with Pergonal (P = 0.45). A trend was seen towards more redness after Pergonal injection (24.0 versus 15.5%; P = 0.08). Post-injection fever was reported in 1.4% with Humegon and in 1.1% with Pergonal (P = 0.80). It was concluded that there are no statistically significant differences between Humegon and Pergonal after i.m. injection with respect to the prevalence of pain and redness at the injection site and of post-injection fever.

A randomized cross-over study comparing pharmacodynamic and metabolic variables of a new combiphasic and a well-established triphasic oral contraceptive.

In an open-label, randomized, cross-over study in 20 subjects, the short-term effects were investigated of Gracial (DSG/EE 7 x 25/40 micrograms/day + 15 x 125/30 micrograms/day) and Trigynon (LNG/EE 6 x 50/30 micrograms/day + 5 x 75/40 micrograms/day + 10 x 125/30 micrograms/day) on plasma concentrations of 17 beta-estradiol and progesterone as well as on carrier proteins (SHBG, CBG, ceruloplasmin), AT-III, carbohydrate metabolism (insulin, glucose, glycosylated proteins) and lipid metabolism (total cholesterol, triglycerides, phospholipids, HDL-C, LDL-C, HDL2-C, HDL3-C, HDL2-C/HDL3-C ratio, Apo A1, Apo B, Apo A1/Apo B ratio). Both preparations adequately and similarly inhibited ovulation in all subjects. Serum levels of carrier proteins were significantly higher with DSG/EE than with LNG/EE, whereas no between-group differences were observed with respect to fasting glucose and insulin, glycosylated proteins (mainly glycosylated albumin) and AT-III activity. DSG/EE showed significantly higher plasma levels than LNG/EE of estrogen-dependent lipid parameters such as triglycerides, HDL-C, HDL2-C, Apo A1, HDL2-C/HDL3-C ratio and Apo A1/Apo B ratio, whereas the levels of LDL-C and Apo B were significantly lower. Both oral contraceptive preparations were equally effective in suppression of follicular development, but combiphasic DSG/EE induced higher plasma levels of carrier proteins and higher plasma levels of potentially anti-atherogenic lipid parameters than did triphasic LNG/EE.

A bioequivalence study of two urinary follicle stimulating hormone preparations: Follegon and Metrodin.

The purpose of this study was to demonstrate bioequivalence between two follicle stimulating hormone (FSH)-only gonadotrophin preparations (Follegon(R) and Metrodin(R)) after a single i.m. injection of IU FSH in-vivo bioactivity. A total of 16 healthy normally cycling females were treated for 7 weeks with a high-dose oral contraceptive containing 50 microg ethinyl oestradiol plus 2.5 mg lynestrenol (Lyndiol(R)) to suppress endogenous gonadotrophin production. After 3 and 5 weeks or oral contraceptive treatment, each subject received 300 IU Follegon or Metrodin in a random order. Frequent blood sampling was performed to measure immunoreactive FSH for pharmacokinetic analysis. After normalization for the immunodose administered, Follegon and Metrodin were bioequivalent with respect to the extent and the rate of absorption, the elimination half-life and plasma clearance per kg. The time taken to reach peak plasma FSH concentrations was shorter with Follegon than with Metrodin. Because bioequivalence was proved for the major pharmacokinetic variables, it can be assumed that Follegon and Metrodin are also equally effective inovulation induction, in-vitro fertilization and embryo transfer programmes and the treatment of male infertility.