Reversible effect of testosterone undecanoate injection on spermatogenesis in rats

Aim: To study the effect of testosterone undecanoate (TU) injection on spermatogenesis in rats. Methods:Twenty adult SD rats received vehicle or TU (8 mg/kg, 19 mg/kg or 625 mg/kg) injection, im, every 15 days for 60days, and another 38 animals received similar treatments for 130 days with half of them undergoing a recovery phase of120 days (5 rats for each treatment). At the end of the treatment, testes were removed and the diameter of the seminif-erous tubules and the number of late elongated spermatids (steps 15-19) per testis were estimated with stereologicalmethods as a measure of the spermatogenic efficiency. Results: Low dose (8 mg/kg) TU treatment virtually hadno effect on spermatogenesis. A dose of 19 mg/kg slightly suppressed spermatogenesis 60 days after treatment, and se-vere suppression occurred after another 70 days of dosing. Spermatogenesis was completely recovered at the end of therecovery phase. Large dose (625 mg/kg) TU treatment did not significantly affect spermatogenesis and was well toler-ated by animals. Conclusion: TU injection reversibly suppresses spermatogenesis in rats.

More than eight years＇ hands-on experience with the novel long-acting parenteral testosterone undecanoate

Testosterone （T） as a compound for treatment of T deficiency has been available for almost 70 years, but the pharmaceutical formulations have been less than ideal. Traditionally, injectable T esters have been used for treatment, but they generate supranormal T levels shortly after the 2-3 weekly injection interval. T levels then decline very rapidly, becoming subnormal during the days preceding the next injection. The rapid fluctuations in plasma T are subjectively experienced as disagreeable. T undecanoate （TU） is a new injectable T preparation with a considerably better pharmacokinetic profile. After two initial injections separated by a 6-week interval, the following intervals between two injections are generally 12 weeks, eventually amounting to a total of four injections per year. Plasma T levels with this preparation are nearly always in the range of normal men, as are its metabolic products estradiol and dihydrotestosterone （DHT）. It reverses the effects of hypogonadism on bone and muscle and metabolic parameters, and on sex functions. It is suitable for male contraception. Its safety profile is excellent because of the continuous normalcy of plasma T levels. No polycythemia has been observed and no adverse effects on lipid profiles. Prostate safety parameters are well within reference limits. TU is a valuable treatment option of androgen deficiency.

Studies on apoptosis of spermatogenic cells in normal fertile men treated with supraphysiological doses of testosterone undecanoate

Aim: To study the anti-spermatogenic mechanism of supra-physiological doses of testosterone undecanoate (TU).Methods: Twenty fertile adult men received four intramuscular injections of TU at monthly intervals, 1000 mg uponadmission and 500 mg for the subsequent injections. The apoptotic germ cells in the semen were studied under light mi-croscope with tenninal deoxynucleotidyl tmnsferase-mediated dUTP-biotin nick end labeling (TUNEL) and Wright-Giem-sa staining methods. Results: After treatment, the sperm density and the number of spermatogenic cells in the semenwere significantly decreased ( P < 0.01), while the apoptotic ratios of spermatocytes and spermatids increased significantly( P <0.01) as compared with the pretreatment levels. Apoptosis was found to be augmented in the whole series of castoffspennatogenic cells. Conclusion: Besides its suppressive effect on spermatogenesis through a negative feed-backmechanism, TU enhances apoptosis of spermatogenic cells, which may be an additional mechanism of its anti-spermato-genic activity. ( Asian J Androl 1999 Sep; 1: 155 - 158)

Study on Differences in Spermatogenic Suppression between Azoospermic and Oligozoospermic Responders Treated with Levonorgestrel Implant Plus Testosterone Undecanoate Injectable in Chinese Men

Objective To investigate possible causes resulting in the differences in the spermatogenesis suppression on individual treated with levonorgestrel (LNG) implants and testosterone undecanoate (TU) injectableMethods Totally 21 Chinese male volunteers were given treatment with LNG implants (four rods, 75 mg/rod) and intramuscular injection of TU (500 mg,bimonthly for 3 times). According to the effects of treatment, they were divided into two groups, namely, azoospermia group (group A) and oligozoospermia group (group O). Then seminal FSH, LH, T and estradiol (E2) were determined by immunoenzymetric assay, while seminal and serum dihydrotachysterol (DHT) and serum sex hormone binding globulin (SHBG) were by radioimmunoassay, and seminal transferrin (Tf) by scatter turbidimetry assay.Results Seminal FSH, LH and serum DHT, SHBG, FTI (T/SHBG ×100) levels were significantly lower in group A than in group O, while higher seminal concentrations ofE2 were observed in azoospermia group.Conclusion The differences in the spermatogenic suppression in Chinese men might be attributed to different rate of peripheral androgen metabolism, variations in serum SHBG levels, 5á-reductase activity and individual aromatase activity during LNG plus TU administration. In addition, seminal sex hormones might be more sensitive indexes to assess the extent of feedback inhibition on hypothalamus-pituitary-testis with exogenous testosterone plus progestogen in the efficacy hormone male contraceptive trials.

Exploring the efficacy of testosterone undecanoate in male children with 5α-reductase deficiency

Importance:Children with 5-alpha-reductase deficiency(5α-RD)and hypospadias present with micropenis,which makes it difficult to obtain sufficient tissue for urethral reconstruction.Objective:We investigated the therapeutic effects of oral testosterone undecanoate and established a standard androgen treatment protocol for patients with 5α-RD with micropenis.Methods:Patients with 5α-RD were treated with oral testosterone undecanoate for 3 months as a course.All patients were treated with no more than 3 courses.If the penile length(PL)reached 2.5 cm(the minimum criterion for surgery)or greater than or equal to−2.5 standard deviations(SDs)(lower limit of normal),testosterone undecanoate was considered to be effective.Results:The median age of 90 patients with 5α-RD was 1.7 years(0.9,3.1 years).The baseline PL was 1.9±0.6 cm before treatment.At the end of the first course,the PL of 63 patients(70%)reached 2.5 cm,and 49 patients(54%)reached greater than or equal to−2.5 SDs.After two treatment courses,the PL of 81 patients(90%)reached 2.5 cm,and 90 patients(100%)reached greater than or equal to−2.5 SDs.After three courses,the PL of all patients reached 2.5 cm,and all patients reached a PL greater than or equal to−2.5 SDs.No abnormal increase was observed in height-SD score,weight-SD score,or ratio of bone age to chronological age during the 1-3-year follow-up.Interpretation:After 3-9 months of treatment,PL increased to the target length.No severe adverse reactions were observed during follow-up.Testosterone undecanoate was safe and effective in children with 5α-RD with micropenis.

Suppression of spermatogenesis by testosterone undecanoate-loaded injectable in situ-forming implants in adult male rats

We have investigated the feasibility of administration of testosterone undecanoate （TU）-Ioaded injectable in situ-forming implant （ISFI） for contraception in adult male Sprague-Dawley rats. Male rats were treated with vehicle, TU-Ioaded ISFIs （540, 270 and 135 mg TU kg-1） or TU injections （45 mg TU kg-1 every 30 days） for 120 days. Fertility tests served for determining infertility or restoration of fertility in treated rats. Serum testosterone concentration, epididymal sperm count, motility, morphology, and histology of the testis were monitored. The TU-Ioaded ISFIs increased serum testosterone levels in rats steadily without fluctuation over 3 months. One month after TU administration, the epididymal sperm count decreased significantly in all experimental groups. After 3 months, the animals treated with 270 and 135 mg kg-~ TU-Ioaded ISFIs were 100% infertile, and no implantation sites were produced in the mated females. However, some of males treated with 540 mg kg-~ ISFI or TU injections were still fertile but numbers of implantation sites were also significantly lower than control values. TU-Ioaded ISFI at an appropriate dose has potential as a long-acting male contraceptive drug that suppresses spermatogenesis consistently over a period of 3 months.

Effectiveness of Testosterone Undecanoate Treatment in Men with Asthenospermia

Objective To assess the effectiveness of testosterone undecanoate on sperm motility and pregnancy incidence in men with asthenospermia. Methods A clinical trial was performed. Fifty men with asthenospermia were included to receive placebo （control group, n=9） or T undecanoate 80 mg/d （study group, n=41）. Pregnancy incidence and sperm characteristics after 1, 2 and 3 months of medication and 3 months after the end of the trial were measured. Results Compared with the placebo, T undecanoate treatment produced a satisfactory improvement of seminal motility （F=55.904, P=0.000）. In study group, the incidence of pregnancy was 28.2% while the incidence of pregnancy in control group was 11.1%. In study group, 26patients took T undecanoate for more than 3 months. In the 3 months, semen volume showed no statistical difference （F=1.206, P=0.312） before and after treatment, sperm concentration （F=0.023, P=0.000） and motility a, b, a ＋b （P=0.000） showed statistical differences. Motility grade a showed significantly higher increment in 2 and 3 months after treatment than 1 month and there was no statistical difference between 2 and 3 months. So did grade b. Conclusion The results indicate that T undecanoate increases semjnal motility, leading to a higher incidence of pregnancy in couples with infertility related to asthenoaspermia.

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is highly prevalent in people with diabetes with no available treatment.AIM To explore the effect of testosterone treatment on liver.Testosterone therapy improves insulin resistance and reduces total body fat,but its impact on the liver remains poorly studied.METHODS This secondary analysis of a 40 wk,randomised,double-blinded,placebocontrolled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging(MRI).RESULTS Of 88 patients enrolled in the index study,39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo.All patients had>5%hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD.Median liver fat at baseline was 15.0%(IQR 11.5%-21.1%)in the testosterone and 18.4%(15.0%-28.9%)in the placebo group.Median ALT was 34units/L(26-38)in the testosterone and 32units/L(25-52)in the placebo group.At week 40,patients receiving testosterone had a median reduction in absolute liver fat of 3.5%(IQR 2.9%-6.4%)compared with an increase of 1.2%in the placebo arm(between-group difference 4.7%P<0.001).After controlling for baseline liver fat,testosterone therapy was associated with a relative reduction in liver fat of 38.3%(95%confidence interval 25.4%-49.0%,P<0.001).CONCLUSION Testosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone.Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified.

Inhibitine Effects of Sino-implant Plus Testosterene Undecanoate(TU) on Spermatogenesis in Chinese Men

The purpose of this study was to use a kind of safe,long acting and reversible hormonal regimen for male contraception .The studied regimen was a subdermal insertion of a two rod implant (Sino implant, each rod containing 75 mg levenorgestrel LNG) in each subject's forearm, followed 3 weeks after by monthly injection of TU (Testosterone Undecanoate 250 mg) for 3 months. Eighteen weeks after implantation, the Sino implant was removed. There were altogether 16 male volunteers recruited in the entire research program. Among them 6 cases reached azoospermia; one case reached oligozoospermia (sperm density <3 million/ml); 5 cases' sperm density declined greatly, the lowest to be 5.7±1.3 million/ml; the other four cases' sperm density also declined, but remained within normal range (above 20 million/ml), the lowest to be 24.5±9.0 million/ml. The duration to reach azoospermia was 16.7±0.5 weeks. The duration to resume to normal range of sperm density was 8.2±2.5 weeks in the subjects with azoospermia and oligozoospermia. In the first two weeks after insertion the LNG release of Sino implant's mean serum LNG level was about 0.38 ng/ml, in the rest of the time the LNG levels in blood was rather constant about 0.24 ng/ml. Routine analyses of blood and urine, liver and kidney functions, and blood chemistry including those parameters (TG,TC,HDL C,LDL C) of lipid metabolism didn't change much throughout the research. All the subjects' libido and sex function were well kept. Clinical observation didn't show any other adverse effects during the research.