Mechanism of Action:
DEPO-TESTOSTERONE delivers testosterone in the form of testosterone cypionate intramuscularly to produce circulating testosterone levels that approximate normal levels (e.g. 10.4 – 34.6 nmol/L [300 - 1000 ng/dL]) seen in healthy young men.
Pharmacodynamics
Testosterone and Hypogonadism: Testosterone and dihydrotestosterone (DHT), endogenous androgens, are responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat distribution.
Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include decreased sexual desire with or without impotence, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics, and osteoporosis. Hypogonadism is a risk factor for osteoporosis in men.
General Androgen Effects: Drugs in the androgen class also promote retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium.
Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens have been reported to stimulate the production of red blood cells by enhancing erythropoietin production.
Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process.
During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH).
Pharmacokinetics
Absorption: Testosterone cypionate is a testosterone ester. Esterification of testosterone at position 17 increases the lipid solubility of the testosterone molecule and prolongs the activity of the molecule by increasing its residence time. Following intramuscular administration in an oily vehicle, testosterone ester is slowly absorbed into the general circulation and then rapidly hydrolysed in plasma to testosterone.
In a randomized cross-over study of six healthy males aged 20-29 years of age, the pharmacokinetics of a single injection of 200 mg testosterone cypionate was compared to that of a single injection of 194 mg testosterone enanthate. Mean serum testosterone concentrations increased sharply to 3 times the basal levels (approximately 1350 ng/dL) at 24 hours and declined gradually to basal levels (approximately 500 ng/dL) by day 10.
A similar observation was noted in a clinical study of replacement therapy with a single intramuscular dose of 200 mg testosterone cypionate in 11 hypogonadal males aged 28-74. Pharmacokinetic analysis showed a three-fold mean increase in serum testosterone concentrations by day 2 (1108 ± 440 ng/dL) and a progressive decline to basal serum levels (360 ± 166 ng/dL) by day 14 for the group.
These pharmacokinetic studies demonstrated the dosing regimen of 200 mg testosterone cypionate every 2 weeks led to initial elevation of serum testosterone into the supraphysiological range and then a gradual decline into the hypogonadal range by the end of the dosing interval.
Distribution: Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen.
Metabolism: There is considerable variation in the half-life of testosterone as reported in the literature, ranging from ten to 100 minutes.
Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase located in the skin, liver, and the urogenital tract of the male. Estradiol is formed by an aromatase enzyme complex in the brain, fat, and testes. DHT binds with greater affinity to SHBG than does testosterone. In many tissues, the activity of testosterone depends on its reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolized to 3-α and 3-β androstanediol.
Excretion: About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.