madman
Super Moderator
1 Introduction
The main indication for androgen therapy is the treatment of androgen deficiency in hypogonadal men. Since such androgen replacement therapy usually involves the life-long administration of testosterone, it is desirable that testosterone formulations be long-acting. The primary goal of androgen replacement therapy is to replicate the physiological actions of endogenous testosterone. This requires not just rectification of deficient androgen levels but also avoiding either supranormal or excessively fluctuating testosterone levels. Thus the practical intent of androgen replacement therapy is to maintain stable, physiological testosterone levels for prolonged periods. The pharmacological properties of testosterone, notably its rapid metabolic inactivation by the liver, have dictated that the achievement of such prolonged androgenic effects requires the development of depot, sustained-release testosterone formulations (Wilson 1980). Nevertheless, even 50 years after the entry of testosterone into the clinical armamentarium (Hamilton 1937; Foss 1939) the quest for a safe, effective, inexpensive, convenient, long-acting androgen preparation with reproducible, zero-order release profile remains an important challenge not yet met. One of the oldest testosterone formulations is the subdermal implant of testosterone pellets which provide stable testosterone levels for at least 4 months after a single implantation (Cantrill et al.1984; Conway et al. 1988). Curiously this cheap and effective treatment modality has been neglected for decades despite its many advantages for androgen replacement therapy.
2 History
3 Formulation and physical features
4 Implantation procedure
5 Absorption
5.1 Mechanism of absorption
5.2 Kinetics of absorption
6 Bioavailability
7 Pharmacokinetics
7.1 Pharmacological studies
7.2 Total and free testosterone levels
Implantation of testosterone pellets gives a highly reproducible and dose-dependent time-course for circulating total and free testosterone (Fig. 5). Total testosterone levels on the 1200 mg dose are higher (p < 0.0001) than those of either 600 mg combination which in turn produced similar (p = 0.95) circulating testosterone levels and time courses. Plasma testosterone levels peaked at the 1st month and gradually declined to return to baseline by 6 months after either 600 mg dose regimen but remained significantly elevated after 6 months following the 1200 mg dose. Plasma-free testosterone was so highly correlated (r = 0.90) with total testosterone that free testosterone levels exhibited virtually the same time course as that of total testosterone. The one exception was that free testosterone levels were significantly higher in the first (but not the second) 3 months after the 6 x 100 mg regimen which had a higher initial surface area compared with the 3 x 200 mg regimen consistent with an effect of initial pellet surface area on early testosterone release rates.
Although many steroid implants (Burris et al. 1988; Diaz-Sanchez et al. 1989) demonstrate an accelerated initial (or "burst") release, this does not occur with testosterone pellet implants. Weekly blood sampling for one month after implantation of 6 x 100 mg testosterone pellets in 15 hypogonadal men (Conway et al.t 988) demonstrated a gradual rise of total and free testosterone and suppression of gonadotropins (Fig.6). Peak testosterone levels were attained between 2 and 4 weeks after implantation. Furthermore, even during daily blood sampling after implantation either 6 x 200 mg (Fig. 7) or 6 x 100 mg (data not shown) pellets indicate an absence of "burst" release by the first day after implantation. Thus the early release of testosterone from pellets is gradual, lacking the "burst" release or overshoot observed with some other testosterone formulations (Burris et al. 1988; Diaz-Sanchez et al. 1989). Although "burst" release is not completely excluded by our observations, if present it would only occur for the first day at most.
8 Pharmacodynamics
8.1 Clinical effects
8.2 LH and FSH suppression
8.3 SHBG
8.4 Biochemistry and hematology
9 Side-effects
10 Clinical use of testosterone pellet implants
10.1 Indications, contra-indications and limitations
10.2 Dose and monitoring
10.3 Comparison with other testosterone formulations
10.4 Costs
11 Future
11.1 Development of pellet implants
11.2 New applications
12 Summary and conclusions
The ideal androgen preparation for long-term androgen replacement therapy would be safe, effective, inexpensive, already marketed, long-acting due to depot properties, and exhibit zero-order release. Such an androgen formulation is not available but the testosterone pellets fulfill many of these criteria and in our opinion are superior to any presently available testosterone preparations.
The testosterone pellets are highly effective, economical, already marketed, and have very long-acting properties and stability of effects with zero-order release pattern. A single implant of 600-1200 mg can provide stable, effective, and well-tolerated androgen replacement for 4-6 or more months. Total and free testosterone levels rise gradually to peak at 1 month and gradually decline over several months before returning to baseline. SHBG levels are unaffected and, in men with primary hypogonadism, gonadotropin levels are markedly suppressed in a mirror image of the testosterone levels. Clinical monitoring of the androgenic effects of the pellets can be achieved by clinical, hormonal, or both methods as for other testosterone preparations. Drawbacks include the requirement for limited minor surgical skills for the implantation procedure. The only significant side-effect is pellet extrusion which will occur following implant procedures in about 5% of cases with the acquisition of some experience.
The main indication for androgen therapy is the treatment of androgen deficiency in hypogonadal men. Since such androgen replacement therapy usually involves the life-long administration of testosterone, it is desirable that testosterone formulations be long-acting. The primary goal of androgen replacement therapy is to replicate the physiological actions of endogenous testosterone. This requires not just rectification of deficient androgen levels but also avoiding either supranormal or excessively fluctuating testosterone levels. Thus the practical intent of androgen replacement therapy is to maintain stable, physiological testosterone levels for prolonged periods. The pharmacological properties of testosterone, notably its rapid metabolic inactivation by the liver, have dictated that the achievement of such prolonged androgenic effects requires the development of depot, sustained-release testosterone formulations (Wilson 1980). Nevertheless, even 50 years after the entry of testosterone into the clinical armamentarium (Hamilton 1937; Foss 1939) the quest for a safe, effective, inexpensive, convenient, long-acting androgen preparation with reproducible, zero-order release profile remains an important challenge not yet met. One of the oldest testosterone formulations is the subdermal implant of testosterone pellets which provide stable testosterone levels for at least 4 months after a single implantation (Cantrill et al.1984; Conway et al. 1988). Curiously this cheap and effective treatment modality has been neglected for decades despite its many advantages for androgen replacement therapy.
2 History
3 Formulation and physical features
4 Implantation procedure
5 Absorption
5.1 Mechanism of absorption
5.2 Kinetics of absorption
6 Bioavailability
7 Pharmacokinetics
7.1 Pharmacological studies
7.2 Total and free testosterone levels
Implantation of testosterone pellets gives a highly reproducible and dose-dependent time-course for circulating total and free testosterone (Fig. 5). Total testosterone levels on the 1200 mg dose are higher (p < 0.0001) than those of either 600 mg combination which in turn produced similar (p = 0.95) circulating testosterone levels and time courses. Plasma testosterone levels peaked at the 1st month and gradually declined to return to baseline by 6 months after either 600 mg dose regimen but remained significantly elevated after 6 months following the 1200 mg dose. Plasma-free testosterone was so highly correlated (r = 0.90) with total testosterone that free testosterone levels exhibited virtually the same time course as that of total testosterone. The one exception was that free testosterone levels were significantly higher in the first (but not the second) 3 months after the 6 x 100 mg regimen which had a higher initial surface area compared with the 3 x 200 mg regimen consistent with an effect of initial pellet surface area on early testosterone release rates.
Although many steroid implants (Burris et al. 1988; Diaz-Sanchez et al. 1989) demonstrate an accelerated initial (or "burst") release, this does not occur with testosterone pellet implants. Weekly blood sampling for one month after implantation of 6 x 100 mg testosterone pellets in 15 hypogonadal men (Conway et al.t 988) demonstrated a gradual rise of total and free testosterone and suppression of gonadotropins (Fig.6). Peak testosterone levels were attained between 2 and 4 weeks after implantation. Furthermore, even during daily blood sampling after implantation either 6 x 200 mg (Fig. 7) or 6 x 100 mg (data not shown) pellets indicate an absence of "burst" release by the first day after implantation. Thus the early release of testosterone from pellets is gradual, lacking the "burst" release or overshoot observed with some other testosterone formulations (Burris et al. 1988; Diaz-Sanchez et al. 1989). Although "burst" release is not completely excluded by our observations, if present it would only occur for the first day at most.
8 Pharmacodynamics
8.1 Clinical effects
8.2 LH and FSH suppression
8.3 SHBG
8.4 Biochemistry and hematology
9 Side-effects
10 Clinical use of testosterone pellet implants
10.1 Indications, contra-indications and limitations
10.2 Dose and monitoring
10.3 Comparison with other testosterone formulations
10.4 Costs
11 Future
11.1 Development of pellet implants
11.2 New applications
12 Summary and conclusions
The ideal androgen preparation for long-term androgen replacement therapy would be safe, effective, inexpensive, already marketed, long-acting due to depot properties, and exhibit zero-order release. Such an androgen formulation is not available but the testosterone pellets fulfill many of these criteria and in our opinion are superior to any presently available testosterone preparations.
The testosterone pellets are highly effective, economical, already marketed, and have very long-acting properties and stability of effects with zero-order release pattern. A single implant of 600-1200 mg can provide stable, effective, and well-tolerated androgen replacement for 4-6 or more months. Total and free testosterone levels rise gradually to peak at 1 month and gradually decline over several months before returning to baseline. SHBG levels are unaffected and, in men with primary hypogonadism, gonadotropin levels are markedly suppressed in a mirror image of the testosterone levels. Clinical monitoring of the androgenic effects of the pellets can be achieved by clinical, hormonal, or both methods as for other testosterone preparations. Drawbacks include the requirement for limited minor surgical skills for the implantation procedure. The only significant side-effect is pellet extrusion which will occur following implant procedures in about 5% of cases with the acquisition of some experience.
