The first published reports on TPI were in the 1940’s making it one of the first, if not the first, forms of bioidentical hormone replacement therapy. Pellets have the highest consistency of delivery of any form of hormone administration. Clinical trials show that TPI results in therapeutic hormone levels within just 24-hours, and most people feel a difference within 24 to 48-hours, although in some it may take up to 14-days. Pellets usually last for 4-months in women and between 4 and 5-months in men. Pellets do not need to be removed, as they completely dissolve over time. In the event of problems the active metabolites estradiol (E2) and DHT can be impeded by 5-alpha-reductase and aromatase inhibitors.
Reported major advantages associated with TPI include:
•Physiological hormone release – healthy young males produce 6-9 mg/day testosterone, the release rate of a 100 mg testosterone implant is ≈ 0.6 mg/day, therefore 12 x 100 mg pellets will provide > 7 mg/day testosterone;
•Elevations of DHT or E2 are uncommon in those whose levels are normal before TRT is begun;
•Suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH) is dose-dependent and correlates with clinical effects. As with other forms of testosterone administration the suppression of LH may cause the testicles to decrease in size, although this is much less common than with injections or creams in the author’s experience. In theory, letrozole (Femara®) may prevent this, but human chorionic gonadotrophin (HCG) is the more common method of maintaining testicular size if desired;
•Lack of weekly swings in testosterone levels (which are commonly seen with intramuscular (IM) injections);
•Testosterone implants help to maintain bone mineral density (BMD) – a single implantation with 1200 mg of testosterone has been shown to be more effective in increasing BMD than oral or IM testosterone in men with primary hypogonadism
•Minimal complications – extrusion <1%-8% (early heavy physical activity involving the gluteal muscles is a predisposing factor for extrusion, thus patients are encouraged to avoid heavy physical activity for 3-days post implantation), minor bleeding 0-2%, minor infection 1-5% - complication rate is related to operator skill;
•There is no scarring to interfere with further implants
•Consistency, compliance (continuation rate of 93%), and convenience – implantation of pellets is a minor procedure (takes approximately 5 minutes) and causes minimal discomfort. Patients require implants just 2 or 3 times a year.
The only real disadvantage associated with TPI is the difficulty in removing pellets if necessary, for example if the patient is diagnosed with prostate cancer while pellets are present. For that reason, at the time of initial evaluation, if prostate specific antigen (PSA) is elevated to the high-normal or above-normal range it is wise to treat with an alternative method of TRT and recheck PSA in 2-3 months. If PSA has remained stable pellet implantation should be safe. If there are any concerns the patient should be referred for a urological consultation.
Male Clinical Studies
Handelsman et al1 studied the pharmacokinetics and pharmacodynamics of implanted testosterone pellets in a prospective, cross-over clinical trial of 43 androgen deficient men. Three different regimens (6 x 100 mg, 6 x 200 mg; and 3 x 200 mg) were compared. Results showed a consistent, near linear release rate, with levels of total testosterone (TT) and free testosterone (fT) peaking at 1-month. Physiological doses were maintained for approximately 4-months with the 600 mg dose and 6-months with the 1200 mg dose. No difference in TT levels was observed between the 6 x 100 mg and 3 x 200 mg pellets in TT. A difference in fT was noted initially however this was not statistically significant after the first insertion. The authors concluded: “We conclude that fused pellets of crystalline testosterone provides very satisfactory depot androgen replacement exhibiting many desirable features for androgen replacement.”
Jockenhövel et al2 conducted a single-dose, non-randomized pharmacokinetic study of 14 hypogonadal men. Participants were implanted with 6 testosterone pellets, each containing 200 mg of fused crystalline testosterone. At the same time the feasibility and side-effects of testosterone pellets were evaluated in another 36 hypogonadal men. Results of the pharmacokinetic study revealed an initial short-lived burst of testosterone release, followed by a stable release level until day 63. Thereafter serum levels of testosterone declined gradually and were close to baseline concentrations by day 300. Therapeutic levels were maintained for up to180 days. Results also showed an initial decline in sex hormone binding globulin (SHBG) levels, an elevation of DHT and E2, and a lower ratio of DHT to testosterone. The only side-effect observed during 112 implantations in the total group of 50 men was 6 local infections, which lead to extrusion of 5 pellets in 3 men. All but one participant (49 of 50 men) preferred testosterone pellets to their previous testosterone medication for TRT. The authors concluded: “Testosterone pellets are the androgen formulation with the longest biological action and strongest pharmacodynamic efficacy in terms of gonadotrophin suppression. The pharmacokinetic features are advantageous compared to other testosterone preparations and the patient acceptance is high.”
Female Clinical Studies
Testosterone has wide ranging biological effects in pre and postmenopausal women, in part because of widespread androgen receptors found in the brain, spinal cord, nerves, breast, bone, muscles, cardiovascular system, gastrointestinal tract, lungs, bladder, vaginal tissue, uterus, skin, hair follicles and adipose tissue. Testosterone also exerts its effect indirectly via aromatization to estrogen in these organs, ovary and adrenal gland. Greenblatt and Suran3 recommended the use of testosterone pellets in women for a variety of different reasons, including:
•Menopausal syndrome in whom estrogen replacement therapy (ERT) has proved unsatisfactory or is contraindicated;
•Dysmenorrheic patient with endometriosis or small fibromyomata (for whom surgery is not feasible);
•Nocturia of endocrine origin;
•Desire to increase libido;
•Palliative measure in patients with advanced carcinoma of the breast;
•In combination with desoxycorticosterone pellets for Addison’s disease.
Testosterone implants in women have been shown to improve lethargy/fatigue, depression, loss of libido, and hot flashes. They have also been found to have a favorable effect on blood pressure, blood lipid profile, and blood clot formation. Indeed, in a review of testosterone implants in postmenopausal women by Sands and Studd,4 the authors conclude: “Androgen replacement therapy is a neglected area of medical practice and further research is needed to identify all women who will benefit from it since studies in menopausal women have shown parenteral administration to be well tolerated and safe. Such therapy is underused and very much under-researched.”
Glaser et al conducted a study to investigate the beneficial effects of continuous testosterone therapy, delivered by subcutaneous implant, in the relief of somatic, psychological and urogenital symptoms in both pre- and postmenopausal women. 300 pre- and postmenopausal women with symptoms of relative androgen deficiency were asked to self-administer the 11-item Menopause