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Author: Kelleher, S, Turner, L, Howe, C, Conway, AJ, Handelsman, DJ

Affiliation: Andrology Unit, Royal Prince Alfred Hospital &, Department of Medicine, University of Sydney,

Australia.

Title: Extrusion of testosterone pellets: a randomized controlled clinical study.

Source: Clinical Endocrinology, 1999 Oct, 51(4):469-71.

Publication Type: Clinical Trial; Randomized Controlled Trial

Subjects: Major Subjects (MeSH): Hormone Replacement Therapy Hypogonadism--drug therapy Testosterone--

administration & dosage

Other Subjects (MeSH): Drug Implants Prospective Studies Treatment Failure

BACKGROUND: It has previously been shown that testosterone implantation is an effective and well accepted form of androgen replacement therapy, but that pellet extrusion was the most frequent side-effect. The present study aimed to reduce the extrusion rate.

OBJECTIVE: To determine whether the washing of testosterone pellets to remove potentially surface-adherent particles decreased the rate of extrusion of pellet implants.

DESIGN: Prospective, randomized parallel group design in a single centre with consecutive procedures to be randomized (1 : 1) into a wash or control group.

PATIENTS: The study included 251 testosterone implantation procedures in men with known androgen deficiency.

MEASUREMENTS: The primary endpoint, extrusion rate per procedure, was evaluated prospectively by telephone contact at 1 week and then 3 and 6 month intervals. Secondary end-points included peri-procedure adverse events (bleeding, skin reaction, excessive discomfort) noted at the time of implant. Bruising, bleeding and infection were also evaluated as later adverse events by telephone and personal follow-up. Explanatory variables recorded as possible covariables included the number of implants used, production batch number of the implants, the operator, as well as other demographic and medical factors.

RESULTS: In the wash group, the extrusion rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects), indicating no evidence of any benefit of the wash procedure (OR = 1. 09 [95% CI 0.47-2.6] per procedure). There was no evidence of benefit in secondary endpoints including total adverse events (7.1%, OR 1.28 [0.44-3.9], bleeding/bruising (8.8%, 1.23 [0.47-3.3]) and infection (4.0%, 1.54 [0.35-7.6]) per procedure. Among men reporting an infection requiring antibiotic treatment according to their own general practitioners, six/ten (60%) subsequently experienced an extrusion. There were no significant differences in extrusion rate between four different operators (P = 0.24) nor among 12 different batches of pellets used during the course of the study (P = 0.77).

CONCLUSIONS: The pellet washing procedure used during implantation does not reduce the subsequent extrusion rate. The higher rate of both primary and secondary adverse events in this prospective study compared with the previous retrospective survey may reflect either more rigorous follow-up or a secular trend.

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Author: Handelsman, DJ, Mackey, MA, Howe, C, Turner, L, Conway, AJ

Title: An analysis of testosterone implants for androgen replacement therapy.

Source: Clinical Endocrinology, 1997 Sep, 47(3):311-6.

Subjects: Major Subjects (MeSH): Hypogonadism--drug therapy Testosterone--administration & dosage

Other Subjects (MeSH): Drug Implants Evaluation Studies Patient Satisfaction Retrospective Studies Testosterone--therapeutic use

Abstract:

OBJECTIVE: To review 13 years of experience using fused crystalline testosterone implants for androgen replacement therapy in order to identify pattern of usage (including continuation rates) and adverse events emerging during therapy and factors associated with adverse events including implant extrusions.

DESIGN: Retrospective review of prospectively collected data on characteristics of patients and implant procedures performed as well as adverse events reported during routine follow-up.

PATIENTS: Over 13 years 973 implant procedures using fused crystalline testosterone implants were performed in 221 men.

MEASUREMENTS: Continuation rates and adverse events such as extrusions, bleeding, infection or others were recorded and analysed in relationship to characteristics of the patient and the implant procedure performed.

RESULTS: Overall rate of adverse events (108/73, 11.1%) was significantly related to increased numbers of implants (4.2 +/- 0.1 vs 4.0 +/- 0.03, P = 0.031) and higher levels of physical activity at work (P = 0.030). The most common adverse effect was extrusion (83/973, 8.5%) which was related to occupational classification (P = 0.033) and increasing work activity (P = 0.044) and occurred more frequently than by chance in multiple (16 vs 3.3 expected) rather than single (65 vs 76.1 expected) episodes. Bleeding (22/973, 2.3%) was significantly associated with an increased number of implants (4.5 +/- 0.2 vs 4.0 +/- 0.03, P = 0.020) but even in the worst cases (3/22) it was of minor clinical importance. Infection was rare (6/973, 0.6%) but occurred more among thinner men. The overall continuation rate was 92.7% increasing from 86% after the first implantation to > 99% after the tenth implant.

CONCLUSIONS: This study demonstrates the very satisfactory clinical acceptability of testosterone pellet implants for androgen replacement therapy within a single unit with experienced operators. The only regular adverse effect is extrusion, which may be related to mechanical factors such as habitual work activity but also possibly procedural factors. Other adverse effects such as bleeding, infection and fibrosis were rare. An improved method of implant delivery would enhance this old but durable technology.

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Author: Handelsman, DJ, Conway, AJ, Boylan, LM

Affiliation: Andrology Unit, Royal Prince Alfred Hospital, Sydney, Australia.

Title: Pharmacokinetics and pharmacodynamics of testosterone pellets in man.

Source: Journal of Clinical Endocrinology and Metabolism, 1990 Jul, 71(1):216-22.

Publication Type: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL

Subjects: Major Subjects (MeSH): Testosterone--pharmacokinetics

Other Subjects (MeSH): Androgens--deficiency Clinical Trials Dose-Response Relationship, Drug Drug Implants

FSH--metabolism Hypogonadism--drug therapy Kinetics LH--metabolism Radioimmunoassay Sex Hormone-

Binding Globulin--metabolism Testosterone--administration & dosage Testosterone--pharmacology

Abstract:

We studied the pharmacokinetics and pharmacodynamics of sc implanted pellets of fused crystalline testosterone. Three different regimens (6 x 100 mg, 6 x 200 mg; and 3 x 200 mg) were compared in a prospective, cross-over clinical trial in which androgen deficient men were administered the three-dose combinations in a randomized starting order at intervals of at least 6 months. Plasma free and total testosterone, sex hormone-binding globulin, LH, and FSH were measured before and at monthly intervals for at least 6 months after 111 pellet implantation in 43 men with hypergonadotropic (n = 22) or hypogonadotropic (n = 21) hypogonadism. Total and free testosterone levels peaked at the first month and were maintained at physiological levels for 4 to 5 (600 mg doses) or 6 (1200 mg dose) months after a single implantation. Absorption of testosterone from 100 mg and 200 mg pellets closely approximated zero-order throughout the effective life of the pellets and exhibited a half-duration of 2.5 months. The estimated rate of release of testosterone was 1.5 (95% confidence limits 1.3-1.6) mg/day.200 mg pellet as determined from direct measurement of residue in pellets recovered after extrusion and confirmed independently from percent absorbed-time plots. The bioavailability of testosterone was virtually complete and the time course was predictable from the total implant dose and, to a lesser extent, total initial surface areas of pellets. Despite wide fluctuations in testosterone, SHBG levels were not changed during 6 months. In men with hypergonadotropic hypogonadism, both LH and FSH levels were uniformly and markedly suppressed by increased testosterone after pellet implants. LH and FSH were highly correlated with each other (r = 0.87) and inversely with total (r = 0.47 and 0.45, respectively) and free (r = 0.46 and 0.47) testosterone levels. Nadir LH levels occurred at 1-3 months (600 mg) and 1-4 months (1200 mg) reaching levels comparable with eugonadal controls. In contrast nadir FSH levels occurred at similar times but remained elevated compared with eugonadal controls. We conclude that fused pellets of crystalline testosterone provides very satisfactory depot androgen replacement exhibiting many desirable features for androgen replacement.

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Author: Conway, AJ, Boylan, LM, Howe, C, Ross, G, Handelsman, DJ

Affiliation: Andrology Unit, Royal Prince Alfred Hospital, Sydney, Australia.

Title: Randomized clinical trial of testosterone replacement therapy in hypogonadal men.

Source: International Journal of Andrology, 1988 Aug, 11(4):247-64.

Subjects: Major Subjects (MeSH): Hypogonadism--drug therapy Testosterone--therapeutic use

Other Subjects (MeSH): Clinical Trials Estradiol--blood FSH--blood LH--blood Random Allocation Sex Hormone-

Binding Globulin--metabolism Testosterone--pharmacokinetics

Abstract:

We have compared the pharmacokinetics and pharmacodynamics of the three commonly used testosterone formulations in a prospective, randomized cross-over clinical trial. Plasma free and total testosterone and their ratio (proportion of unbound testosterone), sex hormone-binding globulin (SHBG), oestradiol, LH and FSH were measured in 15 hypogonadal men (nine hyper- and six hypogonadotrophic) who underwent, in a randomized sequence, three treatment periods each separated by an intervening washout period. The treatments were: (i) intramuscular injection of 250 mg mixed testosterone esters at 2-weekly intervals, (ii) oral testosterone undecanoate 120 mg bd, and (iii) subcutaneous testosterone pellets (6 x 100 mg). Pellet implantation gave the most prolonged effect with free and total testosterone levels being elevated for up to 4 months. This was accompanied by prompt and sustained suppression of plasma LH and FSH, an increase in plasma levels of oestradiol but no change in SHBG levels. In contrast, intramuscular injections induced marked but reproducible week-to-week fluctuations in free and total testosterone, which resulted in a small decrease in plasma SHBG levels, less marked suppression of LH and FSH and a smaller increase in plasma levels of oestradiol. Oral testosterone undecanoate produced the most variable plasma levels of free and total testosterone with a peak in the first treatment week and a fall thereafter and, despite maintenance of testosterone levels within the physiological range, there was no significant suppression of plasma levels of LH and FSH, and oestradiol levels were unchanged but levels of SHBG and total cholesterol were decreased. Free testosterone levels were increased disproportionately during testosterone treatment as the proportion of unbound testosterone was increased by all three treatments. All three testosterone preparations lowered plasma levels of urea and all were without biochemical or haematological toxicity. Reported sexual function was better maintained and side-effects were fewer with parenteral compared with oral treatments. The marked decrease in SHBG and cholesterol levels during oral testosterone undecanoate, when compared with parenteral treatments, occurred despite lesser androgenic effects (suppression of gonadotrophin levels and reported sexual function), which suggests that the liver is exposed to excessive androgenic load via the portal vein during oral treatment with testosterone esters. It is concluded that testosterone pellets give the closest approximation to zero-order (steady-state) delivery conditions for up to 4 months after a single insertion.

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Author: Zacharin, MR, Warne, GL

Affiliation: Department of Endocrinology and Diabetes, Royal Children's Hospital, Parkville, Victoria, Australia.

Title: Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets.

Source: Archives of Disease in Childhood, 1997 Jun, 76(6):495-9.

Language: English Publication Type: CLINICAL TRIAL; JOURNAL ARTICLE

Subjects: Major Subjects (MeSH): Hypogonadism--drug therapy Testosterone--administration & dosage

Other Subjects (MeSH): Bone Development--drug effects Delayed-Action Preparations Drug Implants Emotions

FSH--blood Growth--drug effects Hypogonadism--blood Hypogonadism--physiopathology LH--blood Penis--

growth & development Puberty--drug effects Testosterone--blood Testosterone--therapeutic use

Abstract:

AIMS: Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life-long treatment is indicated.

PATIENTS AND METHODS: Eighteen boys (aged 13.9-17.5 years at the start of treatment)-seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature--were given testosterone pellets (8-10 mg/kg) every six months for 18 months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3, 6, 12, and 18 months. Bone age was measured at 0 and 12 months.

RESULTS: In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10 nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions.

CONCLUSIONS: All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.

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Author: Cantrill, JA, Dewis, P, Large, DM, Newman, M, Anderson, DC

Title: Which testosterone replacement therapy?

Source: Clinical Endocrinology, 1984 Aug, 21(2):97-107.

Subjects: Major Subjects (MeSH): Hypogonadism--therapy Testosterone--administration & dosage

Other Subjects (MeSH): Administration, Oral Androstane-3,17-diol--analogs & derivatives Androstane-3,17-diol--

blood Drug Implants Estradiol--blood Hypogonadism--blood Injections, Intramuscular Stanolone--blood

Testosterone--analogs & derivatives Testosterone--blood Testosterone--therapeutic use

Abstract:

Three different forms of testosterone (T) replacement therapy were compared; they were the intramuscular injection of mixed testosterone esters 250 mg; the subcutaneous implantation of 6 X 100 mg pellets of fused testosterone; and the oral administration of testosterone undecanoate (TU) 80 mg twice daily. Six hypogonadal males were treated with oral TU for an eight week period, during which time serial serum hormonal estimations were performed over 10 h at the initiation and after four and eight weeks of therapy. Serum T levels showed marked variability both between subjects and within the same subject on different occasions. We attribute this to variability in absorption of TU, which is formulated in oleic acid. The overall mean T level calculated from the areas under the profiles of TU was 12.0 nmol/l. Hormone responses to injected T esters were studied in nine hypogonadal males. Serum T rose to supraphysiological peak concentrations (mean 71 nmol/l) 24-48 h after an injection, followed by an exponential decay to reach baseline concentrations after 2-3 weeks. The overall calculated mean T level in subjects receiving testosterone esters 250 mg every three weeks was 27.7 nmol/l. Subcutaneous implantation of testosterone in six hypogonadal men produced a gradual rise in serum T followed by a slow decline, with T levels remaining within the normal range for 4-5 months. The calculated overall mean T level over 21 weeks after implantation was 17.0 nmol/l. Serum oestradiol (E2) levels remained within the normal male range throughout the study periods on both TU and T implant therapy but showed a supraphysiological peak (mean 347 pmol/l) 24-48 h after a T injection. 5 alpha-dihydrotestosterone (DHT) levels appeared to parallel those of T on the three forms of therapy, with DHT:T ratios being highest for TU therapy. This was also true for the target organ metabolite 5 alpha-androstane-3 alpha,17 beta-diol. At the doses studied drug costs were similar for T implantation (every 5 months) and T ester injections (every 3 weeks), but were 7-8 times higher for TU (80 mg twice a day). We conclude that T implantation remains overall the most physiological form of androgen replacement therapy, is generally well accepted and attended by few side effects; TU may have a useful role in the initial phases of therapy.

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Author: Kapetanakis, E, Dmowski, WP, Auletta, F, Scommegna, A

Title: Endocrine and clinical effects of estradiol and testosterone pellets used in long-term   replacement therapy.

Source: International Journal of Gynaecology and Obstetrics, 1982 Oct, 20(5):387-99.

Language: English Publication Type: JOURNAL ARTICLE

Subjects: Major Subjects (MeSH): Estradiol--administration & dosage Estrogens--deficiency Gonadal Dysgenesis--

drug therapy Menopause Menopause, Premature Testosterone--administration & dosage

Other Subjects (MeSH): Drug Implants Drug Therapy, Combination Estradiol--blood Estrone--blood FSH--blood

Gonadal Dysgenesis--blood LH--blood Testosterone--blood

Ten women with estrogen deficiency symptoms because of premature menopause [3], gonadal dysgenesis [3], or surgical menopause [4] received subcutaneous implants consisting of 25--75 mg estradiol (E2) with or without 75 mg testosterone (T). All had elevated plasma FSH, and LH, and low E2 prior to treatment. Plasma levels of FSH, LH, E2, T and estrone (E1) were measured by specific radioimmunoassay techniques prior to treatment, three times a week for the first week and once a week for up to 76 weeks after implantation. Mean plasma E2 levels rose abruptly and reached a maximum of 190 +/- 35 pg/ml within 2 weeks. They fluctuated around 150 pg/ml for 46 weeks, then gradually declined, but remained above pretreatment values for more than 68 weeks. Plasma E1 increased to a lesser extent resulting in E2:E1 ratio between 1 and 5. Elevated FSH and LH titers became suppressed within 4--6 weeks. The lowest average E2 increased occurred after 25 mg implant and was associated with incomplete FSH and LH suppression. There were no differences in maximal E2 levels reached after 50 mg or 75 mg implant, however, after 75 mg implant, E2 levels appeared less variable and were sustained for a longer period of time, averaging 125 pg/ml for 70 weeks. Plasma FSH and LH concentrations were suppressed below pretreatment levels in all patients. The degree of suppression was related to the dose of E2 implanted and, therefore, to plasma E2 levels. The FSH and LH suppression appeared more complete in women with gonadal dysgenesis than in those with premature or natural menopause. Plasma T rose abruptly to a peak mean level of 2.5 +/- 1.6 ng/ml within 2 weeks of implantation. A precipitous and steady decline with return to preimplantation titers between 17th and 18th week were then observed. The E2:E1 ratio during the first 18 weeks after implantation was significantly higher in women who received E2 implant alone than in those who received E2 + T implant. Clinically, all patients had symptomatic improvement within 24--48 hours. Regular withdrawal bleeding followed administration of oral progestogen for up to 76 weeks after implantation in six patients with intact uterus.

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