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.

Clinical impact of LH rises prior to and during ganirelix treatment started on day 5 or on day 6 of ovarian stimulation.

BACKGROUND: We sought to evaluate the incidence and clinical impact of luteinizing hormone (LH) rises prior to and during gonadotropin-releasing hormone (GnRH) antagonist treatment started on day 5 or 6 of ovarian stimulation with recombinant follicle-stimulating hormone (rFSH). METHODS: Pooled data from three trials with the GnRH antagonist ganirelix started on day 5 (n = 961) and from five trials with ganirelix started on day 6 (n = 1135) of ovarian stimulation with rFSH were retrospectively analyzed. RESULTS: The incidence of LH rises (LH ≥ 10.0 IU/L) prior to ganirelix treatment was 2.3% and 6.6% on ganirelix start days 5 and 6, respectively (P < 0.01). During ganirelix treatment this incidence was 1.2% and 2.3%, respectively (P = 0.06). Women with LH rise on day 5 or 6 had a higher ovarian response with more oocytes recovered, mean ± SD, 12.9 ± 8.5 versus no LH rise, 10.2 ± 6.4 (P < 0.01). In women with and without LH rise prior to ganirelix treatment the ongoing pregnancy rates were similar (26.0% vs 29.9%; odds ratio [OR], 0.89; 95% confidence interval [CI], 0.55-1.44). Women with LH rise during ganirelix treatment had a lower ovarian response with 7.5 ± 6.7 oocytes recovered versus no LH rise, 10.2 ± 6.4 (P = 0.02) and a tendancy for a lower chance of ongoing pregnancy (16.7% vs 29.9%; OR, 0.52; 95% CI, 0.21-1.26). CONCLUSIONS: The incidence of early and late LH rises was low but may be further reduced by initiating ganirelix on stimulation day 5 rather than on day 6. In contrast to women with an early LH rise, women with a late LH rise may have a reduced chance of ongoing pregnancy.

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.

Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity.

BACKGROUND: One injection of corifollitropin alfa replaces the first seven daily FSH injections in controlled ovarian stimulation (COS) cycles. Repeated treatment with therapeutic proteins may cause immune responses or hypersensitivity reactions. We assessed the immunogenicity and safety of corifollitropin alfa treatment in up to three COS cycles. METHODS: In this multicentre, phase III uncontrolled trial, patients (>60 kg) started treatment with one injection of 150 µg corifollitropin alfa on cycle Day 2 or 3 of menses and 0.25 mg ganielix on stimulation Day 5 or 6. Primary outcome measures were antibody formation against corifollitropin alfa (using highly sensitive radioimmunoprecipitation assay), hypersensitivity reactions, local tolerance and adverse events (AEs). RESULTS: First, second and third COS cycles were started by 682, 375 and 198 patients, respectively. No clinically relevant immunogenicity or drug-related hypersensitivity was observed. For 192 patients undergoing their third cycle a post-treatment blood sample was negative in the anti-corifollitropin antibody assay, resulting in an upper limit of the one-sided 95% confidence interval (CI) of 1.5%. Most frequent AEs were procedural pain (17.7%, 95% CI: 14.9-20.8%), headache (9.1%, 95% CI: 7.0-11.5%) and pelvic pain (7.6%, 95% CI: 5.7-9.9%). Cumulative ongoing pregnancy rate after three cycles, including frozen-thawed embryo transfer cycles and spontaneous pregnancies, was 61% (95% CI: 56-65%) after censoring for patients who discontinued. CONCLUSIONS: Treatment with corifollitropin alfa can safely and effectively initiate and sustain ovarian stimulation during the first 7 days of COS in normal responder patients undergoing up to three treatment cycles, without concerns of immunogenicity. The trial was registered under ClinicalTrials.gov identifier NCT00696878.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization.

OBJECTIVE: To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN: Phase 3 randomized, double-blind, noninferiority trial. SETTING: Multicenter trial. PATIENT(S): A total of 1,390 women aged 35-42 years. INTERVENTION(S): A single injection of 150 µg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S): Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S): Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S): Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: NCT01144416.

Andropause and quality of life: findings from patient focus groups and clinical experts.

OBJECTIVES: To develop a condition-specific quality of life (QoL) questionnaire to assess the symptoms of the decline in testosterone that occurs as men age, otherwise known as the andropause. METHODS: Two focus groups of patients with low testosterone levels and an expert panel of physicians in the treatment of male testosterone deficiency. RESULTS: The patient focus groups confirmed that men are unlikely to realise they have low testosterone levels until this is diagnosed and that they are unlikely to share their experiences with peers. Both patients and physicians considered decreased energy levels and impaired sexual performance had the greatest adverse impact on well-being. Patients generally felt that testosterone replacement therapy led to improved energy levels and, to a lesser extent, improved libido and erectile function. Evaluation of the responses resulted in the identification of seven key domains (energy, emotional, social, social emotional, mental functioning, physical functioning and sexual functioning) that should be considered when assessing the impact of andropause on QoL. CONCLUSIONS: Understanding the impact of low testosterone levels on QoL is critical to diagnosis and effective treatment. The use of an andropause-specific QoL questionnaire will facilitate quantification of patient experiences and may thus improve subsequent therapy.

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.

Tibolone lowers high density lipoprotein cholesterol by increasing hepatic lipase activity but does not impair cholesterol efflux.

OBJECTIVE: Androgens and other drugs that reduce plasma concentrations of high density lipoprotein (HDL) cholesterol are often considered to be pro-atherogenic. Tibolone lowers HDL-cholesterol by 20% but the clinical significance of this effect is unknown. METHODS: In a randomized, double-blind study, 34 women received 2.5 mg tibolone daily and 34 women received placebo. Serum concentrations of lipids, lipoprotein subclasses and apolipoproteins, together with plasma activities of lipid transfer proteins and lipolytic enzymes and the capacity of plasma to induce cholesterol efflux from cultured cells, were measured. RESULTS: Compared to placebo, tibolone reduced serum concentrations of HDL-cholesterol (-14%), HDL phosphatidylcholine (-14%), apolipoprotein (apo)A-I (-12%), HDL subclasses lipoprotein (Lp)A-I (-20%), HDL-apoE (-16%), pre beta-LpA-I (-10%) and alpha-LpA-I (-12%) and increased hepatic lipase activity (+25%) and HDL sphingomyelin : phosphatidylcholine ratio (10.5%), but did not alter serum concentrations of HDL sphingomyelin, apoA-IV and LpA-I/A-II, lipoprotein lipase, the plasma activities of lecithin : cholesterol acyl transferase, cholesteryl ester transfer protein, phospholipid transfer protein or the plasma capacity to release cholesterol from cultured fibroblasts or Fu5AH hepatocytes. CONCLUSIONS: Tibolone lowers HDL-cholesterol in part by increasing hepatic lipase activity. Conservation of sphingomyelin and apoA-II in HDL, as well as cholesteryl ester transfer protein activity, preserves the capacity of plasma to release cholesterol, despite the lower concentrations of HDL-cholesterol. This may have important implications for the use of steroid effects on HDL concentrations as surrogates for atherosclerosis.

Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects.

OBJECTIVE: Sex differences are found in most components of the insulin resistance syndrome and the associated cardiovascular risk profile. These differences are attributed to sex-specific sex steroid profiles, but the effects of sex steroids on the individual components of the insulin resistance syndrome remain incompletely understood. DESIGN: Prospective, intervention study. SUBJECTS: In 37 young (age range 16-36 years), nonobese [body mass index (BMI) < 29], transsexual subjects, effects of ethinyl oestradiol (100 micro g/day) + cyproterone acetate (100 mg/day) administration were evaluated in 20 male-to-female transsexuals and of testosterone-ester administration [250 mg intramuscularly (i.m.)/2 weeks] in 17 female-to-male transsexuals. MEASUREMENTS: We studied lipid spectrum, postheparin hepatic lipase (HL) and lipoprotein lipase (LPL) activity, blood pressure, glucose utilization (by euglycaemic hyperinsulinaemic clamp), and fat areas (by magnetic resonance imaging) at baseline and during 1-year cross-sex hormone administration. RESULTS: Oestrogens + antiandrogens increased high-density lipoprotein (HDL)-cholesterol and decreased LDL-cholesterol, and HL activity, which are considered beneficial. But this combination also increased triglycerides, blood pressure, subcutaneous fat and visceral fat, and decreased the LDL-particle size, LPL activity and insulin sensitivity, which are all considered detrimental. Testosterone reduced HDL-cholesterol and the LDL-particle size, and increased triglycerides and HL activity. An android fat distribution was induced (i.e. decreased subcutaneous and increased visceral fat). Blood pressure, total and LDL-cholesterol, LPL activity and insulin sensitivity were mainly unaffected. CONCLUSIONS: The effects of cross-sex hormone treatment - in the dosages used in this study - in healthy, nonobese, young transsexual subjects do not show unequivocally that female sex steroids, given in large amounts to male subjects, have beneficial effects on cardiovascular profile and that high dose testosterone administration to female subjects is detrimental with respect to cardiovascular risk.